Heterobicyclic metalloprotease inhibitors

ABSTRACT

The present invention relates generally to azabicyclic containing pharmaceutical agents, and in particular, to azabicyclic metalloprotease inhibiting compounds. More particularly, the present invention provides a new class of azabicyclic MMP-3, MMP-8 and/or MMP-13 inhibiting compounds, which exhibit an increased potency and selectivity in relation to currently known MMP-13, MMP-8 and MMP-3 inhibitors.

This application claims the benefit of U.S. Provisional Application No.60/860,195, filed Nov. 20, 2006, which is hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention relates generally to amide containing azabicyclicmetalloprotease inhibiting compounds, and more particularly toazabicyclic amide MMP-13, MMP-8, MMP-3 and MMP-2 inhibiting compounds.

BACKGROUND OF THE INVENTION

Matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS=a disintegrinand metalloproteinase with thrombospondin motif) are a family ofstructurally related zinc-containing enzymes that have been reported tomediate the breakdown of connective tissue in normal physiologicalprocesses such as embryonic development, reproduction, and tissueremodelling. Over-expression of MMPs and aggrecanases or an imbalancebetween extracellular matrix synthesis and degradation has beensuggested as factors in inflammatory, malignant and degenerative diseaseprocesses. MMPs and aggrecanases are, therefore, targets for therapeuticinhibitors in several inflammatory, malignant and degenerative diseasessuch as rheumatoid arthritis, osteoarthritis, osteoporosis,periodontitis, multiple sclerosis, gingivitis, corneal epidermal andgastric ulceration, atherosclerosis, neointimal proliferation (whichleads to restenosis and ischemic heart failure) and tumor metastasis.

The ADAMTSs are a group of proteases that are encoded in 19 ADAMTS genesin humans. The ADAMTSs are extracellular, multidomain enzymes whosefunctions include collagen processing, cleavage of the matrixproteoglycans, inhibition of angiogenesis and blood coagulationhomoeostasis (Biochem. J. 2005, 386, 15-27; Arthritis Res. Ther. 2005,7, 160-169; Curr. Med. Chem. Anti-Inflammatory Anti-Allergy Agents 2005,4, 251-264).

The mammalian MMP family has been reported to include at least 20enzymes (Chem. Rev. 1999, 99, 2735-2776). Collagenase-3 (MMP-13) isamong three collagenases that have been identified. Based onidentification of domain structures for individual members of the MMPfamily, it has been determined that the catalytic domain of the MMPscontains two zinc atoms; one of these zinc atoms performs a catalyticfunction and is coordinated with three histidines contained within theconserved amino acid sequence of the catalytic domain. MMP-13 isover-expressed in rheumatoid arthritis, osteoarthritis, abdominal aorticaneurysm, breast carcinoma, squamous cell carcinomas of the head andneck, and vulvar squamous cell carcinoma. The principal substrates ofMMP-13 are fibrillar collagens (types I, II, III) and gelatins,proteoglycans, cytokines and other components of ECM (extracellularmatrix).

The activation of the MMPs involves the removal of a propeptide, whichfeatures an unpaired cysteine residue complexed with the catalytic zinc(II) ion. X-ray crystal structures of the complex between MMP-3catalytic domain and TIMP-1 and MMP-14 catalytic domain and TIMP-2 alsoreveal ligation of the catalytic zinc (II) ion by the thiol of acysteine residue. The difficulty in developing effective MMP inhibitingcompounds comprises several factors, including choice of selectiveversus broad-spectrum MMP inhibitors and rendering such compoundsbioavailable via an oral route of administration.

MMP-3 (stromelysin-1; transin-1) is another member of the MMP family(FASEB J. 1991, 5, 2145-2154). Human MMP-3 was initially isolated fromcultured human synoviocytes. It is also expressed by chondrocytes andhas been localized in OA cartilage and synovial tissues (Am. J. Pathol.1989, 135, 1055-64).

MMP-3 is produced by basal keratinocytes in a variety of chronic ulcers.MMP-3 mRNA and Protein were detected in basal keratinocytes adjacent tobut distal from the wound edge in what probably represents the sites ofproliferating epidermis. MMP-3 may thus prevent the epidermis fromhealing (J. Clin. Invest. 1994, 94, 79-88).

MMP-3 serum protein levels are significantly elevated in patients withearly and long-term rheumatoid arthritis (Arthritis Rheum. 2000, 43,852-8) and in osteoarthritis patients (Clin. Orthop. Relat. Res. 2004,428, 272-85) as well as in other inflammatory diseases like systemiclupus erythematosis and ankylosing spondylitis (Rheumatology 2006, 45,414-20).

MMP-3 acts on components of the ECM as aggrecan, fibronectin, gelatin,laminin, elastin, fibrillin and others and on collagens of type III, IV,V, VII, IX, X (Clin. Orthop. Relat. Res. 2004, 428, 272-85). Oncollagens of type II and IX, MMP-3 exhibits telopeptidase activity(Arthritis Res. 2001, 3, 107-13; Clin. Orthop. Relat. Res. 2004, 427,S118-22). MMP-3 can activate other MMP family members such as MMP-1,MMP-7, MMP-8, MMP-9 and MMP-13 (Ann. Rheum. Dis. 2001, 60 Suppl3:iii62-7).

MMP-3 is involved in the regulation of cytokines and chemokines byreleasing TGFβ1 from the ECM, activating TNFα, inactivating IL-1β andreleasing IGF (Nat. Rev. Immunol. 2004, 4, 617-29). A potential role forMMP-3 in the regulation of macrophage infiltration is based on theability of the enzyme to convert active MCP species into antagonisticpeptides (Blood 2002, 100, 1160-7).

MMP-8 (collagenase-2; neutrophil collagenase; EC 3.4.24.34) is anothermember of the MMP family (Biochemistry 1990, 29, 10628-34). Human MMP-8was initially located in human neutrophils (Biochemistry 1990, 29,10620-7). It is also expressed by macrophages, human mucosalkeratinocytes, bronchial epithelial cells, ginigival fibroblasts,resident synovial and articular chondrodrocytes mainly in the course ofinflammatory conditions (Cytokine & Growth Factor Rev. 2006, 17,217-23).

The activity of MMP-8 is tightly regulated and mostly limited to thesites of inflammation. MMP-8 is expressed and stored as an inactivepro-enzyme in the granules of the neutrophils. Only after the activationof the neutrophils by proinflammatory mediators, MMP-8 is released andactivated to exert its function.

MMP-8 plays a key role in the migration of immune cells to the sites ofinflammation. MMP-8 degrades components of the extracellular matrix(ECM) such as collagen type I, II, III, VII, X, cartilage aggrecan,laminin-5, nidogen, fibronectin, proteoglycans and tenascin, therebyfacilitating the cells migration through the ECM barrier. MMP-8 alsoinfluences the biological activity of its substrates. Throughproteolytic processing of the chemokines IL-8, GCP-2, ENA-78, MMP-8increases the chemokines ability to activate the infiltrating immunecells. While MMP-8 inactivates the serine protease inhibitor alpha-1antitrypsin through its cleavage (Eur. J. Biochem. 2003, 270, 3739-49;PloS One 2007, 3, 1-10; Cytokine & Growth Factor Rev. 2006, 17, 217-23).

MMP-8 has been implicated in the pathogenesis of several chronicinflammatory diseases characterized by the excessive influx andactivation of neutrophils, including cystic fibrosis (Am. J. Resprir.Critic. Care Med. 1994, 150, 818-22), rheumatoid arthritis (Clin. Chim.Acta 1996, 129-43), chronic periodontal disease (Annals Med. 2006, 38,306-321) and chronic wounds (J. Surg. Res. 1999, 81, 189-195).

In osteoarthritis patients, MMP-8 protein expression is significantlyelevated in inflamed human articular cartilage in the knee and anklejoints (Lab Invest. 1996, 74, 232-40; J. Biol. Chem. 1996, 271,11023-6).

The levels of activated MMP-8 in BALF is an indicator of the diseaseseverity and correlates with the airway obstruction in patients withasthma, COPD, pulmonary emphysema and bronchiectasis (Lab Invest. 2002,82, 1535-45; Am. J. Respir. Crit. Care Med. 1999, 159, 1985-91; Respir.Med. 2005, 99, 703-10; J. Pathol. 2001, 194, 232-38).

SUMMARY OF THE INVENTION

The present invention relates to a new class of azabicyclic amidecontaining pharmaceutical agents which inhibits metalloproteases. Inparticular, the present invention provides a new class ofmetalloprotease inhibiting compounds that exhibit potent MMP-13inhibiting activity and/or activity towards MMP-8, MMP-3 and MMP-2.

The present invention provides several new classes of amide containingazabicyclic metalloprotease compounds, which are represented by thefollowing general formulas:

wherein all variables in the preceding Formula (I) are as definedhereinbelow.

The azabicyclic metalloprotease inhibiting compounds of the presentinvention may be used in the treatment of metalloprotease mediateddiseases, such as rheumatoid arthritis, osteoarthritis, abdominal aorticaneurysm, cancer (e.g. but not limited to melanoma, gastric carcinoma ornon-small cell lung carcinoma), inflammation, atherosclerosis, multiplesclerosis, chronic obstructive pulmonary disease, ocular diseases (e.g.but not limited to ocular inflammation, retinopathy of prematurity,macular degeneration with the wet type preferred and cornealneovascularization), neurologic diseases, psychiatric diseases,thrombosis, bacterial infection, Parkinson's disease, fatigue, tremor,diabetic retinopathy, vascular diseases of the retina, aging, dementia,cardiomyopathy, renal tubular impairment, diabetes, psychosis,dyskinesia, pigmentary abnormalities, deafness, inflammatory andfibrotic syndromes, intestinal bowel syndrome, allergies, Alzheimersdisease, arterial plaque formation, oncology, periodontal, viralinfection, stroke, atherosclerosis, cardiovascular disease, reperfusioninjury, trauma, chemical exposure or oxidative damage to tissues,chronic wound healing, wound healing, hemorroid, skin beautifying, pain,inflammatory pain, bone pain and joint pain, acne, acute alcoholichepatitis, acute inflammation, acute pancreatitis, acute respiratorydistress syndrome, adult respiratory disease, airflow obstruction,airway hyperresponsiveness, alcoholic liver disease, allograftrejections, angiogenesis, angiogenic ocular disease, arthritis, asthma,atopic dermatitis, bronchiectasis, bronchiolitis, bronchiolitisobliterans, burn therapy, cardiac and renal reperfusion injury, celiacdisease, cerebral and cardiac ischemia, CNS tumors, CNS vasculitis,colds, contusions, cor pulmonae, cough, Crohn's disease, chronicbronchitis, chronic inflammation, chronic pancreatitis, chronicsinusitis, crystal induced arthritis, cystic fibrosis, delayted typehypersensitivity reaction, duodenal ulcers, dyspnea, earlytransplantation rejection, emphysema, encephalitis, endotoxic shock,esophagitis, gastric ulcers, gingivitis, glomerulonephritis, glossitis,gout, graft vs. host reaction, gram negative sepsis, granulocyticehrlichiosis, hepatitis viruses, herpes, herpes viruses, HIV,hypercapnea, hyperinflation, hyperoxia-induced inflammation, hypoxia,hypersensitivity, hypoxemia, inflammatory bowel disease, interstitialpneumonitis, ischemia reperfusion injury, kaposi's sarcoma associatedvirus, liver fibrosis, lupus, malaria, meningitis, multi-organdysfunction, necrotizing enterocolitis, osteoporosis, chronicperiodontitis, periodontitis, peritonitis associated with continuousambulatory peritoneal dialysis (CAPD), pre-term labor, polymyositis,post surgical trauma, pruritis, psoriasis, psoriatic arthritis,pulmatory fibrosis, pulmatory hypertension, renal reperfusion injury,respiratory viruses, restinosis, right ventricular hypertrophy,sarcoidosis, septic shock, small airway disease, sprains, strains,subarachnoid hemorrhage, surgical lung volume reduction, thrombosis,toxic shock syndrome, transplant reperfusion injury, traumatic braininjury, ulcerative colitis, vasculitis, ventilation-perfusionmismatching, and wheeze.

In particular, the azabicyclic metalloprotease inhibiting compounds ofthe present invention may be used in the treatment of MMP-13, MMP-8,MMP-3 and MMP-2 mediated osteoarthritis and may be used for otherMMP-13, MMP-8, MMP-3 and MMP-2 mediated symptoms, inflammatory,malignant and degenerative diseases characterized by excessiveextracellular matrix degradation and/or remodelling, such as cancer, andchronic inflammatory diseases such as arthritis, rheumatoid arthritis,osteoarthritis, atherosclerosis, abdominal aortic aneurysm,inflammation, multiple sclerosis, and chronic obstructive pulmonarydisease, and pain, such as inflammatory pain, bone pain and joint pain.

The present invention also provides azabicyclic metalloproteaseinhibiting compounds that are useful as active ingredients inpharmaceutical compositions for treatment or prevention ofmetalloprotease—especially MMP-13, MMP-8, MMP-3 and MMP-2—mediateddiseases. The present invention also contemplates use of such compoundsin pharmaceutical compositions for oral or parenteral administration,comprising one or more of the azabicyclic metalloprotease inhibitingcompounds disclosed herein.

The present invention further provides methods of inhibitingmetalloproteases, by administering formulations, including, but notlimited to, oral, rectal, topical, intravenous, parenteral (including,but not limited to, intramuscular, intravenous), ocular (ophthalmic),transdermal, inhalative (including, but not limited to, pulmonary,aerosol inhalation), nasal, sublingual, subcutaneous or intraarticularformulations, comprising the azabicyclic metalloprotease inhibitingcompounds by standard methods known in medical practice, for thetreatment of diseases or symptoms arising from or associated withmetalloprotease, especially MMP-13, MMP-8, MMP-3 and MMP-2, includingprophylactic and therapeutic treatment. Although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient. Thecompounds from this invention are conveniently presented in unit dosageform and prepared by any of the methods well-known in the art ofpharmacy.

The azabicyclic metalloprotease inhibiting compounds of the presentinvention may be used in combination with a disease modifyingantirheumatic drug, a nonsteroidal anti-inflammatory drug, a COX-2selective inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid,a biological response modifier or other anti-inflammatory agents ortherapeutics useful for the treatment of chemokines mediated diseases.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the invention relates to a compound having Formula (I):

wherein:

R¹ is selected from cycloalkyl fused aryl, heterocycloalkyl fused aryl,cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl,cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkylfused heteroarylalkyl, and heterocycloalkyl fused heteroarylalkyl,

wherein R¹ is optionally substituted one or more times, or

wherein R¹ is optionally substituted by one R¹⁶ group and optionallysubstituted by one or more R⁹ groups;

R² is selected from hydrogen and alkyl, wherein alkyl is optionallysubstituted one or more times or R¹ and R² when taken together with thenitrogen to which they are attached complete a 3- to 8-membered ringcontaining carbon atoms and optionally containing a heteroatom selectedfrom O, S(O)_(x), or NR⁵⁰ and which is optionally substituted one ormore times;

R⁴ in each occurrence is independently selected from R¹⁰, hydrogen,alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, haloalkyl,CF₃, (C₀-C₆)-alkyl-COR¹⁰, (C₀-C₆)-alkyl-OR¹⁰, (C₀-C₆)-alkyl-NR¹⁰R¹¹,(C₀-C₆)-alkyl-NO₂, (C₀-C₆)-alkyl-CN, (C₀-C₆)-alkyl-S(O)_(y)OR¹⁰,(C₀-C₆)-alkyl-S(O)_(y)NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰CONR¹¹SO₂R³⁰,(C₀-C₆)-alkyl-S(O)_(x)R¹⁰, (C₀-C₆)-alkyl-OC(O)R¹⁰,(C₀-C₆)-alkyl-OC(O)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(═NR¹⁰)NR¹⁰R¹¹,(C₀-C₆)-alkyl-NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(O)OR¹⁰,(C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(O)NR¹⁰SO₂R¹¹,(C₀-C₆)-alkyl-C(O)—NR¹¹—CN, O—(C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹,S(O)_(x)—(C₀-C₆)-alkyl-C(O)OR¹⁰, S(O)_(x)—(C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹,(C₀-C₆)-alkyl-C(O)NR¹⁰—(C₀-C₆)-alkyl-NR¹⁰R¹¹,(C₀-C₆)-alkyl-NR¹⁰—C(O)R¹⁰, (C₀-C₆)-alkyl-NR¹⁰—C(O)OR¹⁰,(C₀-C₆)-alkyl-NR¹⁰—C(O)—NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰—S(O)_(y)NR¹⁰R¹¹,(C₀-C₆)-alkyl-NR¹⁰—S(O)_(y)R¹⁰, O—(C₀-C₆)-alkyl-aryl andO—(C₀-C₆)-alkyl-heteroaryl,

wherein each R⁴ group is optionally substituted one or more times, or

wherein each R⁴ group is optionally substituted by one or more R¹⁴groups, or

wherein optionally two R⁴ groups, when taken together with the nitrogenor carbon to which they are attached complete a 3- to 8-memberedsaturated ring or multicyclic ring or unsaturated ring containing carbonatoms and optionally containing one or more heteroatom independentlyselected from O, S(O)_(x), N, or NR⁵⁰ and which is optionallysubstituted one or more times, or

optionally two R⁴ groups taken together at one saturated carbon atomform ═O, ═S, ═NR¹⁰R¹¹ or ═NOR¹⁰;

R⁵ is independently selected from hydrogen, alkyl, C(O)NR¹⁰R¹¹, aryl,arylalkyl, SO₂NR¹⁰R¹¹ and C(O)OR¹⁰ wherein alkyl, aryl and arylalkyl areoptionally substituted one or more times;

R⁸ is independently selected from hydrogen, alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, R¹⁰ and NR¹⁰R¹¹ wherein alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionallysubstituted one or more times;

R⁹ in each occurrence is independently selected from R¹⁰, hydrogen,alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, CHF₂, CF₃,OR¹⁰, SR¹⁰, COOR¹⁰, CH(CH₃)CO₂H, (C₀-C₆)-alkyl-COR¹⁰,(C₀-C₆)-alkyl-OR¹⁰, (C₀-C₆)-alkyl-NR¹⁰R¹¹, (C₀-C₆)-alkyl-NO₂,(C₀-C₆)-alkyl-CN, (C₀-C₆)-alkyl-S(O)_(y)OR¹⁰, (C₀-C₆)-alkyl-P(O)₂OH,(C₀-C₆)-alkyl-S(O)_(y)NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰CONR¹¹SO₂R³⁰,(C₀-C₆)-alkyl-S(O)_(x)R¹⁰, (C₀-C₆)-alkyl-OC(O)R¹⁰,(C₀-C₆)-alkyl-OC(O)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(═NR¹⁰)NR¹⁰R¹¹,(C₀-C₆)-alkyl-NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰C(═N—CN)NR¹⁰R¹¹,(C₀-C₆)-alkyl-C(═N—CN)NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰C(═N—NO₂)NR¹⁰R¹¹,(C₀-C₆)-alkyl-C(═N—NO₂)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(O)OR¹⁰,(C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(O)NR¹⁰SO₂R¹¹,C(O)NR¹⁰—(C₀-C₆)-alkyl-heteroaryl, C(O)NR¹⁰—(C₀-C₆)-alkyl-aryl,S(O)₂NR¹⁰—(C₀-C₆)-alkyl-aryl, S(O)₂NR¹⁰—(C₀-C₆)-alkyl-heteroaryl,S(O)₂NR¹⁰-alkyl, S(O)₂—(C₀-C₆)-alkyl-aryl,S(O)₂—(C₀-C₆)-alkyl-heteroaryl, (C₀-C₆)-alkyl-C(O)—NR¹¹—CN,O—(C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹, S(O)_(x)—(C₀-C₆)-alkyl-C(O)OR¹⁰,S(O)_(x)—(C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹,(C₀-C₆)-alkyl-C(O)NR¹⁰—(C₀-C₆)-alkyl-NR¹⁰R¹¹,(C₀-C₆)-alkyl-NR¹⁰—C(O)R¹⁰, (C₀-C₆)-alkyl-NR¹⁰—C(O)OR¹⁰,(C₀-C₆)-alkyl-NR¹⁰—C(O)—NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰—S(O)_(y)NR¹⁰R¹¹,(C₀-C₆)-alkyl-NR¹⁰—S(O)_(y)R¹¹, O—(C₀-C₆)-alkyl-aryl andO—(C₀-C₆)-alkyl-heteroaryl,

wherein each R⁹ group is optionally substituted, or

wherein each R⁹ group is optionally substituted by one or more R¹⁴groups;

R¹⁰ and R¹¹ in each occurrence are independently selected from hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, bicycloalkyl,heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, fluoroalkyl,heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl,cycloalkylalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl,spiroheteroalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl andaminoalkyl are optionally substituted one or more times, or R¹⁰ and R¹¹when taken together with the nitrogen to which they are attachedcomplete a 3- to 8-membered ring containing carbon atoms and optionallycontaining a heteroatom selected from O, S(O)_(x), or NR⁵⁰ and which isoptionally substituted one or more times;

R¹⁴ is independently selected from hydrogen, alkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, heterocyclylalkyl and halo, whereinalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocyclylalkylare optionally substituted one or more times.

R¹⁶ is selected from cycloalkyl, heterocycloalkyl, bicycloalkyl,heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl,cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fusedheteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl,spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl,cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkylfused heteroarylalkyl, heterocycloalkyl fused heteroarylalkyl, (i) and(ii):

wherein cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl,spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl,heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl,heterocycloalkyl fused heteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl,spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl,cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkylfused heteroarylalkyl, and heterocycloalkyl fused heteroarylalkyl areoptionally substituted one or more times;

R³⁰ is selected from alkyl and (C₀-C₆)-alkyl-aryl, wherein alkyl andaryl are optionally substituted;

R⁵⁰ in each occurrence is independently selected from hydrogen, alkyl,aryl, heteroaryl, C(O)R⁸⁰, C(O)NR⁸⁰R⁸¹, SO₂R⁸⁰ and SO₂NR⁸⁰R⁸¹, whereinalkyl, aryl, and heteroaryl are optionally substituted one or moretimes;

R⁸⁰ and R⁸¹ in each occurrence are independently selected from hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl,heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl andaminoalkyl are optionally substituted, or R⁸⁰ and R⁸¹ when takentogether with the nitrogen to which they are attached complete a 3- to8-membered ring containing carbon atoms and optionally a heteroatomselected from O, S(O)_(x), —NH, and —N(alkyl) and which is optionallysubstituted one or more times;

E is selected from a bond, CR¹⁰R¹¹, O, NR⁵, S, S═O, S(═O)₂, C(═O),N(R¹⁰)(C═O), (C═O)N(R¹⁰), N(R¹⁰)S(═O)₂, S(═O)₂N(R¹⁰), C═N—OR¹¹,—C(R¹⁰R¹¹)C(R¹⁰R¹¹)—, —CH₂—W¹— and

L_(a) is independently selected from CR⁹ and N;

L_(b) is independently selected from C and N with the proviso, that bothL_(b) are not N, and that the bond between L_(b) and L_(b) is optionallya double bond only if both L_(b) are C;

Q is a 4- to 8-membered ring selected from cycloalkyl, heterocycloalkylor a 5- or 6-membered ring selected from aryl and heteroaryl,

wherein Q is optionally substituted one or more times, or

wherein Q is optionally substituted one or more times with R⁴;

U is selected from C(R⁵R¹⁰), NR⁵, O, S, S═O and S(═O)₂;

W¹ is selected from O, NR⁵, S, S═O, S(═O)₂, N(R¹⁰)(C═O), N(R¹⁰)S(═O)₂and S(═O)₂N(R¹⁰);

X is selected from a bond and (CR¹⁰R¹¹)_(w)E(CR¹⁰R¹¹)_(w);

X¹ is independently selected from O, S, NR¹⁰, N—CN, NCOR¹⁰, N—NO₂, orN—SO₂R¹⁰;

g and h are independently selected from 0-2;

w is selected from 0-4;

x is selected from 0 to 2;

y is selected from 1 and 2;

the dotted line optionally represents a double bond; and

N-oxides, pharmaceutically acceptable salts, prodrugs, formulations,polymorphs, tautomers, racemic mixtures and stereoisomers thereof.

In one embodiment, in conjunction with any above or below embodiments,the compound has the structure:

In another embodiment, in conjunction with any above or belowembodiments, the compound is selected from:

In another embodiment, in conjunction with any above or belowembodiments, the compound is selected from:

In another embodiment, in conjunction with any above or belowembodiments, R¹ is selected from:

wherein:

R¹² and R¹³ are independently selected from hydrogen, alkyl and halo,wherein alkyl is optionally substituted one or more times, or optionallyR¹² and R¹³ together form ═O, ═S, ═NR¹⁰ or ═NOR¹⁰;

R¹⁸ is independently selected from hydrogen, alkyl, haloalkyl,cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN,C(O)NR¹⁰R¹¹, CO₂R¹⁰, OR¹⁰, OCF₃, OCHF₂, NR¹⁰CONR¹⁰R¹¹, NR¹⁰COR¹¹,NR¹⁰SO₂R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, SO₂NR¹⁰R¹¹ and NR¹⁰R¹¹, wherein alkyl,haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroarylare optionally substituted one or more times;

R¹⁹ is independently selected from hydrogen, alkyl, haloalkyl,cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN,C(O)NR¹⁰R¹¹, CO₂R¹⁰, OR¹⁰, OCF₃, OCHF₂, NR¹⁰CONR¹⁰R¹¹, NR¹⁰COR¹¹,NR¹⁰SO₂R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, SO₂NR¹⁰R¹¹ and NR¹⁰R¹¹, wherein alkyl,haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroarylare optionally substituted one or more times, or optionally two R¹⁹groups together at one carbon atom form ═O, ═S, ═NR¹⁰ or ═NOR¹⁰;

R²⁵ is selected from hydrogen, alkyl, cycloalkyl, C(O)NR¹⁰R¹¹ andhaloalkyl, wherein alkyl, cycloalkyl, and haloalkyl are optionallysubstituted one or more times;

J and K are independently selected from CR¹⁰R¹⁸, NR¹⁰, O and S(O)_(x);

D², L², M² and T² are independently selected from CR¹⁸ and N; and

Z is a 5- to 8-membered ring selected from cycloalkyl andheterocycloalkyl wherein cycloalkyl and heterocycloalkyl are optionallysubstituted one or more times.

In another embodiment, in conjunction with any above or belowembodiments, L_(b) is C.

In another embodiment, in conjunction with any above or belowembodiments, L_(a) is N.

In another embodiment, in conjunction with any above or belowembodiments, R¹ is selected from:

any of which are substituted by one or two substituents independentlyselected from C₁₋₂alkyl, C₁₋₂haloalkyl, halo, CN, OMe, OCF₃, OCHF₂.

In another embodiment, in conjunction with any above or belowembodiments, R¹ is selected from:

In another embodiment, in conjunction with any above or belowembodiments, R¹ is selected from:

wherein:

R¹⁸ is independently selected from hydrogen, alkyl, haloalkyl,cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN,C(O)NR¹⁰R¹¹, CO₂R¹⁰, OR¹⁰, OCF₃, OCHF₂, NR¹⁰CONR¹⁰R¹¹, NR¹⁰COR¹¹,NR¹⁰SO₂R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, SO₂NR¹⁰R¹¹ and NR¹⁰R¹¹, wherein alkyl,haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroarylare optionally substituted one or more times;

R¹⁹ is independently selected from hydrogen, alkyl, haloalkyl,cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN,C(O)NR¹⁰R¹¹, CO₂R¹⁰, OR¹⁰, OCF₃, OCHF₂, NR¹⁰CONR¹⁰R¹¹, NR¹⁰COR¹¹,NR¹⁰SO₂R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, SO₂NR¹⁰R¹¹ and NR¹⁰R¹¹, wherein alkyl,haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroarylare optionally substituted one or more times, or optionally two R¹⁹groups together at one carbon atom form ═O, ═S, ═NR¹⁰ or ═NOR¹⁰;

R²⁵ is selected from hydrogen, alkyl, cycloalkyl, CONR¹⁰R¹¹ andhaloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionallysubstituted one or more times;

L², M², and T² are independently selected from CR¹⁸ and N;

D³, G³, L³, M³, and T³ are independently selected from N, CR¹⁸, (i), or(ii),

with the proviso that one of L³, M³, T³, D³, and G³ is (i) or (ii)

B₁ is selected from the group consisting of NR¹⁰, O and S(O)_(x); and

Q² is a 5- to 8-membered ring selected from cycloalkyl,heterocycloalkyl, aryl, and heteroaryl, which is optionally substitutedone or more times with R¹⁹.

In another embodiment, in conjunction with any above or belowembodiments, R¹ is selected from:

In another embodiment, in conjunction with any above or belowembodiments, R¹ is selected from:

In another embodiment, in conjunction with any above or belowembodiments, the compound is selected from:

wherein R¹ is selected from:

In another embodiment, in conjunction with any above or belowembodiments, the compound is selected from

and N-oxides, pharmaceutically acceptable salts, prodrugs, formulations,polymorphs, tautomers, racemic mixtures and stereoisomers thereof.

In another embodiment, in conjunction with any above or belowembodiments, R¹ is selected from:

Another aspect of the invention relates to a pharmaceutical compositioncomprising an effective amount of the compound according to any of theabove or below embodiments.

Another aspect of the invention relates to a method of treating ametalloprotease mediated disease, comprising administering to a subjectin need of such treatment an effective amount of a compound according toany of the above or below embodiments.

In another embodiment, in conjunction with any above or belowembodiments, the disease is selected from rheumatoid arthritis,osteoarthritis, inflammation, atherosclerosis and multiple sclerosis.

Another aspect of the invention relates to a pharmaceutical compositioncomprising:

A) an effective amount of a compound according to any of the above orbelow embodiments;

B) a pharmaceutically acceptable carrier; and

C) a drug, agent or therapeutic selected from: (a) a disease modifyingantirheumatic drug; (b) a nonsteroidal anti-inflammatory drug; (c) aCOX-2 selective inhibitor; (d) a COX-1 inhibitor; (e) animmunosuppressive; (f) a steroid; (g) a biological response modifier;and (h) a small molecule inhibitor of pro-inflammatory cytokineproduction.

Another aspect of the invention relates to a method of inhibiting ametalloprotease enzyme, comprising administering a compound according toany of the above or below embodiments.

In another embodiment, in conjunction with any above or belowembodiments, the metalloproteinase is selected from MMP-2, MMP-3, MMP-8,and MMP-13.

In another embodiment, in conjunction with any above or belowembodiments, the disease is selected from the group consisting of:rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, cancer(e.g. but not limited to melanoma, gastric carcinoma or non-small celllung carcinoma), inflammation, atherosclerosis, chronic obstructivepulmonary disease, ocular diseases (e.g. but not limited to ocularinflammation, retinopathy of prematurity, macular degeneration with thewet type preferred and corneal neovascularization), neurologic diseases,psychiatric diseases, thrombosis, bacterial infection, Parkinson'sdisease, fatigue, tremor, diabetic retinopathy, vascular diseases of theretina, aging, dementia, cardiomyopathy, renal tubular impairment,diabetes, psychosis, dyskinesia, pigmentary abnormalities, deafness,inflammatory and fibrotic syndromes, intestinal bowel syndrome,allergies, Alzheimers disease, arterial plaque formation, oncology,periodontal, viral infection, stroke, atherosclerosis, cardiovasculardisease, reperfusion injury, trauma, chemical exposure or oxidativedamage to tissues, wound healing, hemorroid, skin beautifying, pain,inflammatory pain, bone pain and joint pain, acne, acute alcoholichepatitis, acute inflammation, acute pancreatitis, acute respiratorydistress syndrome, adult respiratory disease, airflow obstruction,airway hyperresponsiveness, alcoholic liver disease, allograftrejections, angiogenesis, angiogenic ocular disease, arthritis, asthma,atopic dermatitis, bronchiectasis, bronchiolitis, bronchiolitisobliterans, burn therapy, cardiac and renal reperfusion injury, celiacdisease, cerebral and cardiac ischemia, CNS tumors, CNS vasculitis,colds, contusions, cor pulmonae, cough, Crohn's disease, chronicbronchitis, chronic inflammation, chronic pancreatitis, chronicsinusitis, crystal induced arthritis, cystic fibrosis, delayted typehypersensitivity reaction, duodenal ulcers, dyspnea, earlytransplantation rejection, emphysema, encephalitis, endotoxic shock,esophagitis, gastric ulcers, gingivitis, glomerulonephritis, glossitis,gout, graft vs. host reaction, gram negative sepsis, granulocyticehrlichiosis, hepatitis viruses, herpes, herpes viruses, HIV,hypercapnea, hyperinflation, hyperoxia-induced inflammation, hypoxia,hypersensitivity, hypoxemia, inflammatory bowel disease, interstitialpneumonitis, ischemia reperfusion injury, kaposi's sarcoma associatedvirus, lupus, malaria, meningitis, multi-organ dysfunction, necrotizingenterocolitis, osteoporosis, chronic periodontitis, periodontitis,peritonitis associated with continuous ambulatory peritoneal dialysis(CAPD), pre-term labor, polymyositis, post surgical trauma, pruritis,psoriasis, psoriatic arthritis, pulmatory fibrosis, pulmatoryhypertension, renal reperfusion injury, respiratory viruses, restinosis,right ventricular hypertrophy, sarcoidosis, septic shock, small airwaydisease, sprains, strains, subarachnoid hemorrhage, surgical lung volumereduction, thrombosis, toxic shock syndrome, transplant reperfusioninjury, traumatic brain injury, ulcerative colitis, vasculitis,ventilation-perfusion mismatching, and wheeze.

Another aspect of the invention relates to the use of a compoundaccording to any of the above or below embodiments for the manufactureof a medicament for treating an metalloprotease mediated disease.

In another embodiment, in conjunction with any of the above or belowembodiments, the metalloprotease mediated disease is selected from thegroup consisting of MMP-2, MMP-3, MMP-8 and MMP-13 mediated diseases.

The specification and claims contain listing of species using thelanguage “selected from . . . and . . . ” and “is . . . or . . . ”(sometimes referred to as Markush groups). When this language is used inthis application, unless otherwise stated it is meant to include thegroup as a whole, or any single members thereof, or any subgroupsthereof. The use of this language is merely for shorthand purposes andis not meant in any way to limit the removal of individual elements orsubgroups as needed.

The terms “alkyl” or “alk”, as used herein alone or as part of anothergroup, denote optionally substituted, straight and branched chainsaturated hydrocarbon groups, preferably having 1 to 10 carbons in thenormal chain, most preferably lower alkyl groups. Exemplaryunsubstituted such groups include methyl, ethyl, propyl, isopropyl,n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl,4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl,dodecyl and the like. Exemplary substituents may include, but are notlimited to, one or more of the following groups: halo, alkoxy,alkylthio, alkenyl, alkynyl, aryl (e.g., to form a benzyl group),cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl(—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl(NH₂—CO—), substituted carbamoyl ((R¹⁰)(R¹¹)N—CO— wherein R¹⁰ or R¹¹ areas defined below, except that at least one of R¹⁰ or R¹¹ is nothydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (—SH).

The terms “lower alk” or “lower alkyl” as used herein, denote suchoptionally substituted groups as described above for alkyl having 1 to 4carbon atoms in the normal chain.

The term “alkoxy” denotes an alkyl group as described above bondedthrough an oxygen linkage (—O—).

The term “alkenyl”, as used herein alone or as part of another group,denotes optionally substituted, straight and branched chain hydrocarbongroups containing at least one carbon to carbon double bond in thechain, and preferably having 2 to 10 carbons in the normal chain.Exemplary unsubstituted such groups include ethenyl, propenyl,isobutenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl,decenyl, and the like. Exemplary substituents may include, but are notlimited to, one or more of the following groups: halo, alkoxy,alkylthio, alkyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxy orprotected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy,alkylcarbonyl, carbamoyl (NH₂—CO—), substituted carbamoyl((R¹⁰)(R¹¹)N—CO— wherein R¹⁰ or R¹¹ are as defined below, except that atleast one of R¹⁰ or R¹¹ is not hydrogen), amino, heterocyclo, mono- ordialkylamino, or thiol (—SH).

The term “alkynyl”, as used herein alone or as part of another group,denotes optionally substituted, straight and branched chain hydrocarbongroups containing at least one carbon to carbon triple bond in thechain, and preferably having 2 to 10 carbons in the normal chain.Exemplary unsubstituted such groups include, but are not limited to,ethynyl, propynyl, butyryl, pentynyl, hexynyl, heptynyl, octynyl,nonynyl, decynyl, and the like. Exemplary substituents may include, butare not limited to, one or more of the following groups: halo, alkoxy,alkylthio, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, hydroxy orprotected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy,alkylcarbonyl, carbamoyl (NH₂—CO—), substituted carbamoyl)((R¹⁰)(R¹¹)N—CO— wherein R¹⁰ or R¹¹ are as defined below, except that atleast one of R¹⁰ or R¹¹ is not hydrogen), amino, heterocyclo, mono- ordialkylamino, or thiol (—SH).

The term “cycloalkyl”, as used herein alone or as part of another group,denotes optionally substituted, saturated cyclic hydrocarbon ringsystems, containing one ring with 3 to 9 carbons. Exemplaryunsubstituted such groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclodecyl, and cyclododecyl. Exemplary substituents include, but arenot limited to, one or more alkyl groups as described above, or one ormore groups described above as alkyl substituents.

The term “bicycloalkyl”, as used herein alone or as part of anothergroup, denotes optionally substituted, saturated cyclic bridgedhydrocarbon ring systems, desirably containing 2 or 3 rings and 3 to 9carbons per ring. Exemplary unsubstituted such groups include, but arenot limited to, adamantyl, bicyclo[2.2.2]octane, bicyclo[2.2.1]heptaneand cubane. Exemplary substituents include, but are not limited to, oneor more alkyl groups as described above, or one or more groups describedabove as alkyl substituents.

The term “spiroalkyl”, as used herein alone or as part of another group,denotes optionally substituted, saturated hydrocarbon ring systems,wherein two rings of 3 to 9 carbons per ring are bridged via one carbonatom. Exemplary unsubstituted such groups include, but are not limitedto, spiro[3.5]nonane, spiro[4.5]decane or spiro[2.5]octane. Exemplarysubstituents include, but are not limited to, one or more alkyl groupsas described above, or one or more groups described above as alkylsubstituents.

The term “spiroheteroalkyl”, as used herein alone or as part of anothergroup, denotes optionally substituted, saturated hydrocarbon ringsystems, wherein two rings of 3 to 9 carbons per ring are bridged viaone carbon atom and at least one carbon atom is replaced by a heteroatomindependently selected from N, O and S. The nitrogen and sulfurheteroatoms may optionally be oxidized. Exemplary unsubstituted suchgroups include, but are not limited to,1,3-diaza-spiro[4.5]decane-2,4-dione. Exemplary substituents include,but are not limited to, one or more alkyl groups as described above, orone or more groups described above as alkyl substituents.

The terms “ar” or “aryl”, as used herein alone or as part of anothergroup, denote optionally substituted, homocyclic aromatic groups,preferably containing 1 or 2 rings and 6 to 12 ring carbons. Exemplaryunsubstituted such groups include, but are not limited to, phenyl,biphenyl, and naphthyl. Exemplary substituents include, but are notlimited to, one or more nitro groups, alkyl groups as described above orgroups described above as alkyl substituents.

The term “heterocycle” or “heterocyclic system” denotes a heterocyclyl,heterocyclenyl, or heteroaryl group as described herein, which containscarbon atoms and from 1 to 4 heteroatoms independently selected from N,O and S and including any bicyclic or tricyclic group in which any ofthe above-defined heterocyclic rings is fused to one or moreheterocycle, aryl or cycloalkyl groups. The nitrogen and sulfurheteroatoms may optionally be oxidized. The heterocyclic ring may beattached to its pendant group at any heteroatom or carbon atom whichresults in a stable structure. The heterocyclic rings described hereinmay be substituted on carbon or on a nitrogen atom.

Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolinyl, benzoxazolyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, isatinoyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,oxindolyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl.

Further examples of heterocycles include, but not are not limited to,“heterobicycloalkyl” groups such as 7-oxa-bicyclo[2.2.1]heptane,7-aza-bicyclo[2.2.1]heptane, and 1-aza-bicyclo[2.2.2]octane.

“Heterocyclenyl” denotes a non-aromatic monocyclic or multicyclichydrocarbon ring system of about 3 to about 10 atoms, desirably about 4to about 8 atoms, in which one or more of the carbon atoms in the ringsystem is/are hetero element(s) other than carbon, for example nitrogen,oxygen or sulfur atoms, and which contains at least one carbon-carbondouble bond or carbon-nitrogen double bond. Ring sizes of rings of thering system may include 5 to 6 ring atoms. The designation of the aza,oxa or thia as a prefix before heterocyclenyl define that at least anitrogen, oxygen or sulfur atom is present respectively as a ring atom.The heterocyclenyl may be optionally substituted by one or moresubstituents as defined herein. The nitrogen or sulphur atom of theheterocyclenyl may also be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. “Heterocyclenyl” as used hereinincludes by way of example and not limitation those described inPaquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A.Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9;“The Chemistry of Heterocyclic Compounds, A series of Monographs” (JohnWiley & Sons, New York, 1950 to present), in particular Volumes 13, 14,16, 19, and 28; and “J. Am. Chem. Soc.”, 82:5566 (1960), the contentsall of which are incorporated by reference herein. Exemplary monocyclicazaheterocyclenyl groups include, but are not limited to,1,2,3,4-tetrahydrohydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl,1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl,3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Exemplaryoxaheterocyclenyl groups include, but are not limited to,3,4-dihydro-2H-pyran, dihydrofuranyl, and fluorodihydrofuranyl. Anexemplary multicyclic oxaheterocyclenyl group is7-oxabicyclo[2.2.1]heptenyl.

“Heterocyclyl,” or “heterocycloalkyl,” denotes a non-aromatic saturatedmonocyclic or multicyclic ring system of about 3 to about 10 carbonatoms, desirably 4 to 8 carbon atoms, in which one or more of the carbonatoms in the ring system is/are hetero element(s) other than carbon, forexample nitrogen, oxygen or sulfur. Ring sizes of rings of the ringsystem may include 5 to 6 ring atoms. The designation of the aza, oxa orthia as a prefix before heterocyclyl define that at least a nitrogen,oxygen or sulfur atom is present respectively as a ring atom. Theheterocyclyl may be optionally substituted by one or more substituentswhich may be the same or different, and are as defined herein. Thenitrogen or sulphur atom of the heterocyclyl may also be optionallyoxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.

“Heterocyclyl” as used herein includes by way of example and notlimitation those described in Paquette, Leo A.; “Principles of ModernHeterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularlyChapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds,A series of Monographs” (John Wiley & Sons, New York, 1950 to present),in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”,82:5566 (1960). Exemplary monocyclic heterocyclyl rings include, but arenot limited to, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and thelike.

“Heteroaryl” denotes an aromatic monocyclic or multicyclic ring systemof about 5 to about 10 atoms, in which one or more of the atoms in thering system is/are hetero element(s) other than carbon, for examplenitrogen, oxygen or sulfur. Ring sizes of rings of the ring systeminclude 5 to 6 ring atoms. The “heteroaryl” may also be substituted byone or more substituents which may be the same or different, and are asdefined herein. The designation of the aza, oxa or thia as a prefixbefore heteroaryl define that at least a nitrogen, oxygen or sulfur atomis present respectively as a ring atom. A nitrogen atom of a heteroarylmay be optionally oxidized to the corresponding N-oxide. Heteroaryl asused herein includes by way of example and not limitation thosedescribed in Paquette, Leo A.; “Principles of Modern HeterocyclicChemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3,4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series ofMonographs” (John Wiley & Sons, New York, 1950 to present), inparticular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”,82:5566 (1960). Exemplary heteroaryl and substituted heteroaryl groupsinclude, but are not limited to, pyrazinyl, thienyl, isothiazolyl,oxazolyl, pyrazolyl, furazanyl, pyrrolyl, 1,2,4-thiadiazolyl,pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine,imidazo[2,1-b]thiazolyl, benzofurazanyl, azaindolyl, benzimidazolyl,benzothienyl, thienopyridyl, thienopyrimidyl, pyrrolopyridyl,imidazopyridyl, benzoazaindole, 1,2,3-triazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, benzthiazolyl, dioxolyl, furanyl, indolyl, indolizinyl,isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, oxazinyl,oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyridazinyl,pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinazolinyl,quinolinyl, tetrazinyl, tetrazolyl, 1,3,4-thiadiazolyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,thiatriazolyl, thiazinyl, thiazolyl, thienyl, 5-thioxo-1,2,4-diazolyl,thiomorpholino, thiophenyl, thiopyranyl, triazolyl and triazolonyl.

The phrase “fused” means, that the group, mentioned before “fused” isconnected via two adjacent atoms to the ring system mentioned after“fused” to form a bicyclic system. For example, “heterocycloalkyl fusedaryl” includes, but is not limited to, 2,3-dihydro-benzo[1,4]dioxine,4H-benzo[1,4]oxazin-3-one, 3H-Benzooxazol-2-one and3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one.

The term “amino” denotes the radical —NH₂ wherein one or both of thehydrogen atoms may be replaced by an optionally substituted hydrocarbongroup. Exemplary amino groups include, but are not limited to,n-butylamino, tert-butylamino, methylpropylamino and ethyldimethylamino.

The term “cycloalkylalkyl” denotes a cycloalkyl-alkyl group wherein acycloalkyl as described above is bonded through an alkyl, as definedabove. Cycloalkylalkyl groups may contain a lower alkyl moiety.Exemplary cycloalkylalkyl groups include, but are not limited to,cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl,cyclopropylethyl, cyclopentylethyl, cyclohexylpropyl, cyclopropylpropyl,cyclopentylpropyl, and cyclohexylpropyl.

The term “arylalkyl” denotes an aryl group as described above bondedthrough an alkyl, as defined above.

The term “heteroarylalkyl” denotes a heteroaryl group as described abovebonded through an alkyl, as defined above.

The term “heterocyclylalkyl,” or “heterocycloalkylalkyl,” denotes aheterocyclyl group as described above bonded through an alkyl, asdefined above.

The terms “halogen”, “halo”, or “hal”, as used herein alone or as partof another group, denote chlorine, bromine, fluorine, and iodine.

The term “haloalkyl” denotes a halo group as described above bondedthough an alkyl, as defined above. Fluoroalkyl is an exemplary group.

The term “aminoalkyl” denotes an amino group as defined above bondedthrough an alkyl, as defined above.

The phrase “bicyclic fused ring system wherein at least one ring ispartially saturated” denotes an 8- to 13-membered fused bicyclic ringgroup in which at least one of the rings is non-aromatic. The ring grouphas carbon atoms and optionally 1-4 heteroatoms independently selectedfrom N, O and S. Illustrative examples include, but are not limited to,indanyl, tetrahydronaphthyl, tetrahydroquinolyl and benzocycloheptyl.

The phrase “tricyclic fused ring system wherein at least one ring ispartially saturated” denotes a 9- to 18-membered fused tricyclic ringgroup in which at least one of the rings is non-aromatic. The ring grouphas carbon atoms and optionally 1-7 heteroatoms independently selectedfrom N, O and S. Illustrative examples include, but are not limited to,fluorene, 10,11-dihydro-5H-dibenzo[a,d]cycloheptene and2,2a,7,7a-tetrahydro-1H-cyclobuta[a]indene.

The term “pharmaceutically acceptable salts” refers to derivatives ofthe disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Examplestherefore may be, but are not limited to, sodium, potassium, choline,lysine, arginine or N-methyl-glucamine salts, and the like.

The pharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as, but not limited to, hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric, nitric and the like; and the salts prepared fromorganic acids such as, but not limited to, acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two. Organic solventsinclude, but are not limited to, nonaqueous media like ethers, ethylacetate, ethanol, isopropanol, or acetonitrile. Lists of suitable saltsare found in Remington's Pharmaceutical Sciences, 18th ed., MackPublishing Company, Easton, Pa., 1990, p. 1445, the disclosure of whichis hereby incorporated by reference.

The phrase “pharmaceutically acceptable” denotes those compounds,materials, compositions, and/or dosage forms which are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof human beings and animals without excessive toxicity, irritation,allergic response, or other problem or complication commensurate with areasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” denotes media generallyaccepted in the art for the delivery of biologically active agents tomammals, e.g., humans. Such carriers are generally formulated accordingto a number of factors well within the purview of those of ordinaryskill in the art to determine and account for. These include, withoutlimitation: the type and nature of the active agent being formulated;the subject to which the agent-containing composition is to beadministered; the intended route of administration of the composition;and, the therapeutic indication being targeted. Pharmaceuticallyacceptable carriers include both aqueous and non-aqueous liquid media,as well as a variety of solid and semi-solid dosage forms. Such carrierscan include a number of different ingredients and additives in additionto the active agent, such additional ingredients being included in theformulation for a variety of reasons, e.g., stabilization of the activeagent, well known to those of ordinary skill in the art. Non-limitingexamples of a pharmaceutically acceptable carrier are hyaluronic acidand salts thereof, and microspheres (including, but not limited topoly(D,L)-lactide-co-glycolic acid copolymer (PLGA), poly(L-lactic acid)(PLA), poly(caprolactone (PCL) and bovine serum albumin (BSA)).Descriptions of suitable pharmaceutically acceptable carriers, andfactors involved in their selection, are found in a variety of readilyavailable sources, e.g., Remington's Pharmaceutical Sciences, 17th ed.,Mack Publishing Company, Easton, Pa., 1985, the contents of which areincorporated herein by reference.

Pharmaceutically acceptable carriers particularly suitable for use inconjunction with tablets include, for example, inert diluents, such ascelluloses, calcium or sodium carbonate, lactose, calcium or sodiumphosphate; disintegrating agents, such as croscarmellose sodium,cross-linked povidone, maize starch, or alginic acid; binding agents,such as povidone, starch, gelatin or acacia; and lubricating agents,such as magnesium stearate, stearic acid or talc. Tablets may beuncoated or may be coated by known techniques includingmicroencapsulation to delay disintegration and adsorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample celluloses, lactose, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with non-aqueousor oil medium, such as glycerin, propylene glycol, polyethylene glycol,peanut oil, liquid paraffin or olive oil.

The compositions of the invention may also be formulated as suspensionsincluding a compound of the present invention in admixture with at leastone pharmaceutically acceptable excipient suitable for the manufactureof a suspension. In yet another embodiment, pharmaceutical compositionsof the invention may be formulated as dispersible powders and granulessuitable for preparation of a suspension by the addition of suitableexcipients.

Carriers suitable for use in connection with suspensions includesuspending agents, such as sodium carboxymethylcellulose,methylcellulose, hydroxypropyl methylcelluose, sodium alginate,polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wettingagents such as a naturally occurring phosphatide (e.g., lecithin), acondensation product of an alkylene oxide with a fatty acid (e.g.,polyoxyethylene stearate), a condensation product of ethylene oxide witha long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), acondensation product of ethylene oxide with a partial ester derived froma fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitanmonooleate); and thickening agents, such as carbomer, beeswax, hardparaffin or cetyl alcohol. The suspensions may also contain one or morepreservatives such as acetic acid, methyl and/or n-propylp-hydroxy-benzoate; one or more coloring agents; one or more flavoringagents; and one or more sweetening agents such as sucrose or saccharin.

Cyclodextrins may be added as aqueous solubility enhancers. Preferredcyclodextrins include hydroxypropyl, hydroxyethyl, glucosyl, maltosyland maltotriosyl derivatives of α-, β-, and γ-cyclodextrin. The amountof solubility enhancer employed will depend on the amount of thecompound of the present invention in the composition.

The term “formulation” denotes a product comprising the activeingredient(s) and the inert ingredient(s) that make up the carrier, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical formulations of the presentinvention encompass any composition made by admixing a compound of thepresent invention and a pharmaceutical carrier.

The term “N-oxide” denotes compounds that can be obtained in a knownmanner by reacting a compound of the present invention including anitrogen atom (such as in a pyridyl group) with hydrogen peroxide or aperacid, such as 3-chloroperoxy-benzoic acid, in an inert solvent, suchas dichloromethane, at a temperature between about −10-80° C., desirablyabout 0° C.

The term “polymorph” denotes a form of a chemical compound in aparticular crystalline arrangement. Certain polymorphs may exhibitenhanced thermodynamic stability and may be more suitable than otherpolymorphic forms for inclusion in pharmaceutical formulations.

The compounds of the invention can contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers, ordiastereomers. According to the invention, the chemical structuresdepicted herein, and therefore the compounds of the invention, encompassall of the corresponding enantiomers and stereoisomers, that is, boththe stereomerically pure form (e.g., geometrically pure,enantiomerically pure, or diastereomerically pure) and enantiomeric andstereoisomeric mixtures.

The term “racemic mixture” denotes a mixture that is about 50% of oneenantiomer and about 50% of the corresponding enantiomer relative to allchiral centers in the molecule. Thus, the invention encompasses allenantiomerically-pure, enantiomerically-enriched, and racemic mixturesof compounds of Formulas (I) and (II).

Enantiomeric and stereoisomeric mixtures of compounds of the inventioncan be resolved into their component enantiomers or stereoisomers bywell-known methods. Examples include, but are not limited to, theformation of chiral salts and the use of chiral or high performanceliquid chromatography “HPLC” and the formation and crystallization ofchiral salts. See, e.g., Jacques, J., et al., Enantiomers, Racemates andResolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al.,Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of CarbonCompounds (McGraw-Hill, N.Y., 1962); Wilen, S. H., Tables of ResolvingAgents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of NotreDame Press, Notre Dame, Ind., 1972); Stereochemistry of OrganicCompounds, Ernest L. Eliel, Samuel H. Wilen and Lewis N. Manda (1994John Wiley & Sons, Inc.), and Stereoselective Synthesis A PracticalApproach, Mihaly Nogradi (1995 VCH Publishers, Inc., NY, N.Y.).Enantiomers and stereoisomers can also be obtained from stereomerically-or enantiomerically-pure intermediates, reagents, and catalysts bywell-known asymmetric synthetic methods.

“Substituted” is intended to indicate that one or more hydrogens on theatom indicated in the expression using “substituted” is replaced with aselection from the indicated group(s), provided that the indicatedatom's normal valency is not exceeded, and that the substitution resultsin a stable compound. When a substituent is keto (i.e., ═O) group, then2 hydrogens on the atom are replaced.

Unless moieties of a compound of the present invention are defined asbeing unsubstituted, the moieties of the compound may be substituted. Inaddition to any substituents provided above, the moieties of thecompounds of the present invention may be optionally substituted withone or more groups independently selected from:

C₁-C₄ alkyl;

C₂-C₄ alkenyl;

C₂-C₄ alkynyl;

CF₃;

halo;

OH;

O—(C₁-C₄ alkyl);

OCH₂F;

OCHF₂;

OCF₃;

ONO₂;

OC(O)—(C₁-C₄ alkyl);

OC(O)—(C₁-C₄ alkyl);

OC(O)NH—(C₁-C₄ alkyl);

OC(O)N(C₁-C₄ alkyl)₂;

OC(S)NH—(C₁-C₄ alkyl);

OC(S)N(C₁-C₄ alkyl)₂;

SH;

S—(C₁-C₄ alkyl);

S(O)—(C₁-C₄ alkyl);

S(O)₂—(C₁-C₄ alkyl);

SC(O)—(C₁-C₄ alkyl);

SC(O)O—(C₁-C₄ alkyl);

NH₂;

N(H)—(C₁-C₄ alkyl);

N(C₁-C₄ alkyl)₂;

N(H)C(O)—(C₁-C₄ alkyl);

N(CH₃)C(O)—(C₁-C₄ alkyl);

N(H)C(O)—CF₃;

N(CH₃)C(O)—CF₃;

N(H)C(S)—(C₁-C₄ alkyl);

N(CH₃)C(S)—(C₁-C₄ alkyl);

N(H)S(O)₂—(C₁-C₄ alkyl);

N(H)C(O)NH₂;

N(H)C(O)NH—(C₁-C₄ alkyl);

N(CH₃)C(O)NH—(C₁-C₄ alkyl);

N(H)C(O)N(C₁-C₄ alkyl)₂;

N(CH₃)C(O)N(C₁-C₄ alkyl)₂;

N(H)S(O)₂NH₂);

N(H)S(O)₂NH—(C₁-C₄ alkyl);

N(CH₃)S(O)₂NH—(C₁-C₄ alkyl);

N(H)S(O)₂N(C₁-C₄ alkyl)₂;

N(CH₃)S(O)₂N(C₁-C₄ alkyl)₂;

N(H)C(O)O—(C₁-C₄ alkyl);

N(CH₃)C(O)O—(C₁-C₄ alkyl);

N(H)S(O)₂O—(C₁-C₄ alkyl);

N(CH₃)S(O)₂O—(C₁-C₄ alkyl);

N(CH₃)C(S)NH—(C₁-C₄ alkyl);

N(CH₃)C(S)N(C₁-C₄ alkyl)₂;

N(CH₃)C(S)O—(C₁-C₄ alkyl);

N(H)C(S)NH₂;

NO₂;

CO₂H;

CO₂—(C₁-C₄ alkyl);

C(O)N(H)OH;

C(O)N(CH₃)OH;

C(O)N(CH₃)OH;

C(O)N(CH₃)O—(C₁-C₄ alkyl);

C(O)N(H)—(C₁-C₄ alkyl);

C(O)N(C₁-C₄ alkyl)₂;

C(S)N(H)—(C₁-C₄ alkyl);

C(S)N(C₁-C₄alkyl)₂;

C(NH)N(H)—(C₁-C₄ alkyl);

C(NH)N(C₁-C₄ alkyl)₂;

C(NCH₃)N(H)—(C₁-C₄ alkyl);

C(NCH₃)N(C₁-C₄ alkyl)₂;

C(O)—(C₁-C₄ alkyl);

C(NH)—(C₁-C₄ alkyl);

C(NCH₃)—(C₁-C₄ alkyl);

C(NOH)—(C₁-C₄ alkyl);

C(NOCH₃)—(C₁-C₄ alkyl);

CN;

CHO;

CH₂OH;

CH₂O—(C₁-C₄ alkyl);

CH₂NH₂;

CH₂N(H)—(C₁-C₄ alkyl);

CH₂N(C₁-C₄alkyl)₂;

aryl;

heteroaryl;

cycloalkyl; and

heterocyclyl.

In some cases, a ring substituent may be shown as being connected to thering by a bond extending from the center of the ring. The number of suchsubstituents present on a ring is indicated in subscript by a number.Moreover, the substituent may be present on any available ring atom, theavailable ring atom being any ring atom which bears a hydrogen which thering substituent may replace. For illustrative purposes, if variableR^(X) were defined as being:

this would indicate a cyclohexyl ring bearing five R^(X) substituents.The R^(X) substituents may be bonded to any available ring atom. Forexample, among the configurations encompassed by this are configurationssuch as:

These configurations are illustrative and are not meant to limit thescope of the invention in any way.

Biological Activity

The inhibiting activity towards different metalloproteases of theheterocyclic metalloprotease inhibiting compounds of the presentinvention may be measured using any suitable assay known in the art. Astandard in vitro assay for measuring the metalloprotease inhibitingactivity is described in Examples 1700 to 1706. The heterocyclicmetalloprotease inhibiting compounds show activity towards MMP-2, MMP-3,MMP-8, MMP-12, MMP-13, ADAMTS-4 and/or ADAMTS-5.

The heterocyclic metalloprotease inhibiting compounds of the inventionhave an MMP-13 inhibition activity (IC₅₀ MMP-13) ranging from below 0.2nM to about 20 μM, and typically, from about 0.2 nM to about 1 μM.Heterocyclic metalloprotease inhibiting compounds of the inventiondesirably have an MMP inhibition activity ranging from about 0.2 nM toabout 20 nM. Table 1 lists typical examples of heterocyclicmetalloprotease inhibiting compounds of the invention that have anMMP-13 activity lower than 100 nM (Group A) and from 100 nM to 20 μM(Group B).

TABLE 1 Summary of MMP-13 Activity for Compounds Group Ex. # A 1, 2/1,2/3, 2/4, 2/5, 2/7, 2/9, 2/10, 2/11, 2/20, 2/21, 2/22, 2/23, 2/28, 2/39,2/46, 2/51, 2/55, 2/57, 2/62, 2/69, 2/70, 2/74, 2/86, 2/93, 2/98, 2/101,2/110, 2/111, 2/115, 2/138, 2/149, 2/157, 2/160, 2/179, 2/180, 2/185,2/186, 2/193, 2/194, 2/198, 2/201, 2/221, 2/265, 2/271, 2/275, 2/281,2/373, 2/379, 3, 4/3, 4/12, 4/13, 5, 8, 8/1, 9, 11, 14, 15, 16, 17, 19,20a, 20c, 21, 23b, 24, 29/1, 35, 36, 36/2, 36/8, 36/12, 39/1, 39/22,39/23, 39/24 B 2/6, 2/27, 2/43, 2/50, 2/65, 2/134, 2/136, 2/164, 2/205,4/1, 4/2, 13/1, 20b, 25, 31/1, 38, 39/3, 39/6, 39/12, 39/13, 39/21

Some heterocyclic metalloprotease inhibiting compounds of the inventionhave an MMP-8 inhibition activity (IC₅₀ MMP-8) ranging from below 5 nMto about 20 μM, and typically, from about 10 nM to about 2 μM.Heterocyclic metalloprotease inhibiting compounds of the inventiondesirably have an MMP inhibition activity ranging below 100 nM. Table 2lists typical examples of heterocyclic metalloprotease inhibitingcompounds of the invention that have an MMP-8 activity lower than 250 nM(Group A) and from 250 nM to 20 μM (Group B).

TABLE 2 Summary of MMP-8 Activity for Compounds Group Ex. # A 2/1, 2/9,2/10, 2/11, 2/21, 2/23, 2/26, 2/39, 2/43, 2/46, 2/55, 2/69, 2/70, 2/74,2/93, 2/149, 2/156, 2/157, 2/160, 2/183, 2/194, 2/199, 2/221, 2/275,2/373, 4/3, 4/8, 4/13, 5, 8, 9, 14, 16, 17, 19, 20c, 21, 29/1, 35, 36/2,36/6, 36/12, 36/13, 39/22 B 2/3, 2/5, 2/6, 2/7, 2/15, 2/17, 2/20, 2/22,2/27, 2/28, 2/49, 2/51, 2/57, 2/62, 2/86, 2/98, 2/101, 2/105, 2/110,2/115, 2/134, 2/185, 2/86, 2/265, 36, 39/24

Some heterocyclic metalloprotease inhibiting compounds of the inventionhave an MMP-3 inhibition activity (IC₅₀ MMP-3) ranging from below 10 nMto about 20 μM, and typically, from about 50 nM to about 2 μM.Heterocyclic metalloprotease inhibiting compounds of the inventiondesirably have an MMP inhibition activity ranging below 100 nM. Table 3lists typical examples of heterocyclic metalloprotease inhibitingcompounds of the invention that have an MMP-3 activity lower than 250 nM(Group A) and from 250 nM to 20 μM (Group B).

TABLE 3 Summary of MMP-3 Activity for Compounds Group Ex. # A 2/1, 2/9,2/10, 2/21, 2/23, 2/26, 2/49, 2/51, 2/71, 2/74, 2/86, 2/91, 2/98, 2/134,2/185, 2/186, 2/265, 4/13, 9, 19, 35 B 2/11, 2/20, 2/39, 2/46, 2/55,2/93, 2/105, 2/110, 2/160, 2/183, 2/221, 2/271, 2/373, 4/12, 14, 29/1,36, 36/3, 39/13

The synthesis of metalloprotease inhibiting compounds of the inventionand their biological activity assay are described in the followingexamples which are not intended to be limiting in any way.

Schemes

Provided below are schemes according to which compounds of the presentinvention may be prepared.

In some embodiments the compounds of Formula (I) and (II) aresynthesized by the general methods shown in Scheme 1 to Scheme 3.

Route A

An carbonic acid and amino substituted compound (e.g. 4-amino-nicotinicacid) is condensed (e.g. EtOH/reflux) with chloro-oxo-acetic acid ethylester as previously described e.g. in WO2005/105760 in pyridine to givean oxazine ethyl ester (Scheme 1). This intermediate is then convertedinto the corresponding pyrimidine derivative using a suitable reagent(e.g. NH₄OAc, HOAc, EtOH/80° C.). For example, when ring Q is a pyridinering. The compound can be obtained according this route A.

Route B

An ester and amino substituted compound (e.g. 2-amino-benzoic acid ethylester) is condensed (e.g. 4N HCl, dioxane/50° C.) with ethylcyanoformate as previously described e.g. in WO2005/105760, to give a1,3-pyrimidine-4-one ethyl ester (Scheme 1).

Route C

An carboxamide and amino substituted compound (e.g. 2-amino-benzamide)is condensed with an suitable reagent (e.g oxalic acid diethyl ester oracetic acid anhydride as described in DD272079A1 or chloro-oxo-aceticacid ethyl ester as described in J. Med. Chem. 1979, 22(5), 505-510) togive a 1,3-pyrimidine-4-one ethyl ester (Scheme 1).

Saponification (e.g. aqueous LiOH) of the 1,3-pyrimidine-4-onederivative of Scheme 1 above gives the corresponding bicyclic carboxylicacid (Scheme 2). Activated acid coupling (e.g. EDCl/HOAt) with R¹R²NH(e.g. 6-aminomethyl-4H-benzo[1,4]oxazin-3-one) in a suitable solventgives the desired amide. The saponification/coupling step can becombined by stirring the ester with the free amine at elevatedtemperature (e.g. 200° C., 15 min) under microwave irradiation.

A substituted ketone (e.g. tetrahydrothiophen-3-one) is condensed (e.g.toluene/reflux with Dean-Stark apparatus) with ethyl cyanoacetate,acetic acid and ammonium acetate to afford the desired ethyl ester-cyanosubstituted double bond. (Scheme 3). This intermediate is then convertedinto the corresponding thiophene derivative using suitable reagents(e.g. sulphur, Et₂NH, EtOH/50° C.) as previously described e.g. in J.prakt. Chem. 1973, 315, 39-43 or Monatsh. Chem. 2001, 132, 279-293.

The Knoevenagel/cyclisation step can be combined by stirring the ketonewith ethyl cyanoacetate, sulphur and a base (e.g. Et₃N) in a suitablesolvent (e.g EtOH/50° C.), following the Gewald type reaction asdescribed e.g. in J. prakt. Chem. 1973, 315, 39-43 or Bioorg. Med. Chem.2002, 10, 3113-3122.

In compounds, where the one L_(b) in formula (I) is a nitrogen atom, thefollowing procedure can be applied (Scheme 4).

For example, N-(pyrazol-3-yl)acetamide acetate can be cyclizised withcarbonic acid diethyl ester to 2-methylpyrazolo[1,5a]-s-triazine-4-one(J. Heterocycl. Chem. 1985, 22, 601-634) and further oxidized to thecorresponding acid (e.g. by SeO₂ and then oxone).

In ring Q of the product in Scheme 1 to Scheme 4, further functionalgroup manipulation can be applied (e.g. J. March, Advanced OrganicChemistry, Wiley&Sons), e.g. palladium catalyzed halogen-cyanideexchange or nucleophilic substitution.

EXAMPLES AND METHODS

All reagents and solvents were obtained from commercial sources and usedwithout further purification. Proton spectra (¹H-NMR) were recorded on a400 MHz and a 250 MHz NMR spectrometer in deuterated solvents.Purification by column chromatography was performed using silica gel,grade 60, 0.06-0.2 mm (chromatography) or silica gel, grade 60,0.04-0.063 mm (flash chromatography) and suitable organic solvents asindicated in specific examples. Preparative thin layer chromatographywas carried out on silica gel plates with UV detection.

Preparative Examples are directed to intermediate compounds useful inpreparing the compounds of the present invention.

Preparative Example 1

Step A

2-Methyl-6-nitro-benzoic acid (4.72 g) was dissolved in dry CH₂Cl₂ andDMF (3 drops) and thionyl chloride (3 mL) was added. The mixture wasstirred for 4 h at 40° C., evaporated, coevaporated with toluene anddissolved in ethanol. The mixture was stirred at 70° C. overnight andthen evaporated. The solid was dissolved in 6 N HCl and SnCl₂.2H₂O (15g) was added. The mixture was stirred for 2 h at room temperature,evaporated to give the title compound (4.86 g; quant.) which was usedwithout further purification.

Preparative Example 2

Step A

4-Oxo-3,4-dihydro-quinazoline-2-carboxylic acid ethyl ester (710 mg) wasdissolved in conc. H₂SO₄ and cooled to 5° C., then conc. HNO₃ (4 mL) wasadded. After 15 min the mixture was quenched by adding ice. Theprecipitate was filtered, washed with water and dried to give the titlecompound (809 mg; 94%). [MH]⁺=264.

Preparative Example 2/1 to 2/3

Following similar procedures as described in the Preparative Example 2except using the ethyl esters indicated in Table I.1 below, thefollowing compounds were prepared.

TABLE I.1 Ex. # Amine product yield 2/1

77% [MH]⁺ = 270 2/2

70% [MH]⁺ = 356 2/3

81% [MH]⁺ = 328

Preparative Example 3

Step A

2-Aminonicotinic acid (2.5 g) was suspended in dry pyridine (40 mL) andethyloxalyl chloride (4 mL) was added under ice cooling. The ice bathwas removed and the mixture was stirred for 1 h at room temperature,then heated to 50° C. for 2 h, cooled and evaporated. After adding waterto the residue, the solid was filtered to give the title compound (3.17g; 80%) as a colorless solid. [MH]⁺=221.

Step B

The intermediate from step A above (3.17 g), NH₄OAc (1.11 g) and AcOH(330 μL) was dissolved in EtOH and heated to reflux for 1 h. Aftercooling, the precipitate was triturated with 0.1N hydrochloric acid,filtered and washed with few water and dried to give the title compound(314 mg; 10%) as a colorless solid. [MH]⁺=220.

Preparative Example 3a

Step A

3-Amino-isonicotinic acid (500 mg) was suspended in dry pyridine (8 mL)and ethyloxalyl chloride (2 mL) was added under ice cooling. The icebath was removed and the mixture was stirred for 1 h at roomtemperature, then heated to 50° C. for 2 h, cooled and evaporated. Afteradding water to the residue, the solid was filtered and dissolved inacetic anhydride (10 mL) and heated to reflux to give the title compoundwhich was used for the next step without further purification.[MH]⁺=221.

Step B

The intermediate from step A above, NH₄OAc (400 mg) and AcOH (150 μL)was dissolved in EtOH (10 mL) and heated to reflux for 1 h. Aftercooling, the precipitate was titurated with 0.1N hydrochloric acid,filtered and washed with few water and dried to give the title compound.[MH]⁺=220.

Preparative Example 4

Step A

2-Amino-thiophene-3-carboxylic acid methyl ester (1.1 g) was dissolvedin a 4M solution of HCl in 1,4-dioxane (20 mL) and cyanoacetic acidethyl ester (0.85 mL) was added. The mixture was stirred at 40° C. for 3hours, concentrated and purified by extraction with ethyl acetate froman aqueous solution to afford the title compound (420 mg, 26%).[MH]⁺=225.

Preparative Examples 5/1 to 5/114

Following similar procedures as described in the Preparative Examples 4except using the amines indicated in Table I.2 below, the followingcompounds were prepared.

TABLE I.2 Ex. # Amine product yield 5/1 

77% [MH]⁺ = 239 5/2 

49% [MH]⁺ = 233 5/3 

n.d. [MH]⁺ = 213 5/4 

54% [MH]⁺ = 297/299 5/5 

>99%  [MH]⁺ = 311 5/6 

95% [MH]⁺ = 237 5/8 

>99%  [MH]⁺ = 253 5/9 

71% [MH]⁺ = 311 5/11 

99% [MH]⁺ = 253 5/13 

56% [MH]⁺ = 253 5/14 

56% [MH]⁺ = 297/299 5/15 

99% [MH]⁺ = 345 5/16 

90% [MH]⁺ = 287 5/17 

92% [MH]⁺ = 287 5/18 

88% [MH]⁺ = 277 5/19 

99% [MH]⁺ = 253 5/20 

83% [MH]⁺ = 275 5/21 

75% [MH]⁺ = 307 5/22 

99% [MH]⁺ = 281 5/23 

n.d. [MH]⁺ = 281 5/24 

96% [MH]⁺ = 223 5/25 

75% [MH]⁺ = 307 5/26 

83% [MH]⁺ = 279 5/27 

40% [MH]⁺ = 249 5/28 

33% [MH]⁺ = 235 5/29 

85% [MH]⁺ = 237 5/30 

60% [MH]⁺ = 279 5/31 

75% [MH]⁺ = 261 5/32 

72% [MH]⁺ = 319 5/33 

89% [MH]⁺ = 293 5/34 

77% [MH]⁺ = 281 5/37 

n.d. [MH]⁺ = 281 5/38 

95% [MH]⁺ = 291 5/39 

26% [MH]⁺ = 301 5/40 

98% [MH]⁺ = 335 5/42 

85% [MH]⁺ = 315 5/44 

99% [MH]⁺ = 331 5/44 

35% [MH]⁺ = 223 5/46 

16% [MH]⁺ = 302 5/50 

87% [MH]⁺ = 315 5/52 

100%  [MH]⁺ = 267 5/54 

86% [MH]⁺ = 240 5/55 

31% [MH]⁺ = 225 5/56 

34% [MH]⁺ = 285 5/57 

57% [MH]⁺ = 377 5/58 

84% [MH]⁺ = 267 5/61 

100%  [MH]⁺ = 311 5/62 

100%  [MH]⁺ = 302 5/65 

84% [MH]⁺ = 240 5/66 

75% [MH]⁺ = 283 5/67 

87% [MH]⁺ = 325 5/68 

59% [MH]⁺ = 303 5/70 

20% [MH]⁺ = 339 5/75 

90% [MH]⁺ = 311 5/77 

50% [MH]⁺ = 287 5/78 

60% [MH]⁺ = 233 5/79 

20% [MH]⁺ = 277 5/80 

68% [MH]⁺ = 210 5/81 

30% [MH]⁺ = 210 5/82 

23% [MH]⁺ = 295 5/83 

50% [MH]⁺ = 227 5/85 

30% [MH]⁺ = 237 5/86 

87% [MH]⁺ = 250 5/90 

n.d. [MH]⁺ = 308 5/92 

n.d. [MH]⁺ 329 5/93 

n.d. [MH]⁺ = 329 5/94 

n.d. [MH]⁺ = 304 5/97 

21% [MH]⁺ = 322 5/98 

68% [MH]⁺ = 322 5/100

n.d. [MH]⁺ = 255 5/101

n.d. [MH]⁺ = n.d. 5/102

n.d. [MH]⁺ = n.d. 5/103

n.d. [MH]⁺ = n.d. 5/104

n.d. [MH]⁺ = n.d. 5/105

n.d. [MH]⁺ = n.d. 5/107

n.d. [MH]⁺ = n.d. 5/108

n.d. [MH]⁺ = n.d. 5/109

n.d. [MH]⁺ = n.d. 5/110

n.d. [MH]⁺ = 209 5/111

50% [MH]⁺ = 237 5/112

40% [MH]⁺ = 343 5/113

66% [MH]⁺ = 239 5/114

72% [MH]⁺ = 225

Preparative Example 6

Step A

To an ice cooled solution of commercially available4-Oxo-3,4-dihydro-quinazoline-2-carboxylic acid ethyl ester (400 mg) indry DMF (10 mL) were successively added a 1M solution of NaHDMS in THF(2.2 mL) and methyl iodide (1.3 g). The cooling bath was removed and theresulting mixture was stirred at room temperature overnight.Concentration and purification by chromatography (silica,cyclohexane/EtOAc) afforded the title compound as a colorless solid (370mg, 87%). [MH]⁺=233.

Preparative Example 7

Step A

To a solution of the preparative example 5/1 above (3.69 g) in aceticacid (80 mL) was added bromine (4 mL) at room temperature. After 1.5 hthe reaction was evaporated, water was added, residue was filtered andwashed with water and dried to give the title compound (4.86 g; 99%).[MH]⁺=317/319.

Preparative Example 7/1

Following similar procedures as described in the Preparative Example 7except using the educt derivative indicated in Table I.3 below, thefollowing compounds were prepared.

TABLE I.3 Ex. # Educt product yield 7/1

58% [MH]⁺ = 389/391

Preparative Example 8

Step A

A solution of the preparative example 5/4 above (120 mg) andtributylvinyltin (160 mg), palladium tetrakis(triphenylphosphine) (55mg) in THF (2 mL) was heated in microwave at 160° C. for 30 min. Thesolution was concentrated and purified by chromatography (silica,hexane/EtOAc) to afford the title compound (100 mg, 29%). [MH]⁺=245.

Step B

A solution of the intermediate from Step A above (30 mg) and palladiumon charcoal in methanol (2 mL) was hydrogenated for 1 h. The solutionwas filtered through a bed of celite and concentrated to afford thetitle compound (28 mg, 98%). [MH]⁺=247.

Preparative Example 9

Step A

A solution of the commercially available 4-Isopropyl-phenylamine (1.35g) and N-Bromosuccinimide (2.0 g) in benzene (20 mL) was stirred at roomtemperature. After 12 h, the precipitated solid was filtered off, andthe filtrate was concentrated and purified by chromatography (silica,hexane/EtOAc) to afford the title compound (1.8 g, 89%). [MH]⁺=214.

Step B

A solution of the intermediate from Step A above (800 mg), xantphos (36mg), Pd₂(dba)₃ (20 mg), triethylamine (1.4 mL) in methanol (10 mL) washeated in autoclave under carbon monoxide at 50 psi at 100° C. for 6 h.The solution was concentrated and purified by chromatography (silica,hexane/EtOAc) to afford the title compound (360 mg, 49%). [MH]⁺=194.

Preparative Example 10/1 and 10/3

Following similar procedures as described in the Preparative Example 9except using the aniline derivative indicated in Table I.4 below, thefollowing compounds were prepared.

TABLE I.4 Ex. # Aniline product yield 10/1

80% [MH]⁺ = 208 10/3

24% [MH]⁺ = 285

Preparative Example 11

Step A

To a solution of the Preparative Example 4 above (420 mg) in THF (20 mL)was added 1M aqueous LiOH (5 mL). The resulting mixture was stirred atroom temperature overnight, concentrated and neutralized with 1M aqueousHCl. The residue was filtered off and used without further purification(55 mg, 15%). [MH]⁺=197.

Preparative Examples 12/1-12/110

Following a similar procedure as described in the Preparative Example 11except using the ester indicated in Table I.5 below, the followingcompounds were prepared.

TABLE I.5 Ex. # Ester product Yield 12/1 

85% [MH]⁺ = 191 12/2 

88% [MH]⁺ = 211 12/3 

n.d. [MH]⁺ = 289/291 12/4 

93% [MH]⁺ = 205 12/5 

n.d. [MH]⁺ = 197 12/6 

99% [MH]⁺ = 269/271 12/7 

71% [MH]⁺ = 283 12/8 

91% [MH]⁺ = 209 12/10

>99% [MH]⁺ = 225 12/11

>99% [MH]⁺ = 283 12/14

47% [MH]⁺ = 206 12/15

28% [MH]⁺ = 225 12/17

94% [MH]⁺ = 225 12/18

93% [MH]⁺ = 269 271 12/19

85% [MH]⁺ = 317 12/20

94% [MH]⁺ = 259 12/21

78% [MH]⁺ = 259 12/22

55% [MH]⁺ = 249 12/23

47% [MH]⁺ = 225 12/24

62% [MH]⁺ = 192 12/25

98% [MH]⁺ = 279 12/26

n.d. [MH]⁺ = 205 12/27

51% [MH]⁺ = 253 12/28

85% [MH]⁺ = 253 12/29

48% [MH]⁺ = 195 12/30

36% [MH]⁺ = 236 12/31

71% [MH]⁺ = 251 12/32

91% [MH]⁺ = 217 12/33

90% [MH]⁺ = 219 12/34

86% [MH]⁺ = 221 12/35

96% [MH]⁺ = 207 12/36

92% [MH]⁺ = 209 12/37

88% [MH]⁺ = 227 12/38

86% [MH]⁺ = 233 12/39

85% [MH]⁺ = 247 12/40

97% [MH]⁺ = 291 12/41

85% [MH]⁺ = 265 12/42

>99% [MH]⁺ = 253 12/45

85% (2 steps) [MH]⁺ = 253 12/46

75% [MH]⁺ = 263 12/47

Quant. [MH]⁺ = 273 12/48

38% [MH]⁺ = 307 12/50

62% [MH]⁺ = 287 12/52

73% [MH]⁺ = 303 12/53

53% [MH]⁺ = 195 12/55

27% [MH]⁺ = 274 12/59

91% [MH]⁺ = 288 12/61

69% [MH]⁺ = 239 12/63

n.d. [MH]⁺ = 181 12/64

n.d. [MH]⁺ = 197 12/65

60% [MH]⁺ = 257 12/66

95% [MH]⁺ = 349 12/67

91% [MH]⁺ = 239 12/70

n.d. [MH]⁺ = 283 12/71

n.d. [MH]⁺ = 255 12/72

97% [MH]⁺ = 274 12/74

18% over 3 steps [MH]⁺ = 192 12/75

63% [MH]⁺ = 242 12/76

96% [MH]⁺ = 328 12/78

Quant. [MH]⁺ = 212 12/79

n.d. [MH]⁺ = 241 12/80

45% [MH]⁺ = 297 12/81

74% [MH]⁺ = 361/363 12/82

90% [MH]⁺ = 275 12/83

74% [MH]⁺ = 314 12/88

n.d. [MH]⁺ = 353/355/357 12/90

95% [MH]⁺ = 283 12/95

n.d. [MH]⁺ = 280 12/98

n.d. [MH]⁺ = 301 12/99

n.d. [MH]⁺ = 301  12/100

41% [MH]⁺ = 276  12/101

84% [MH]⁺ = 315  12/102

92% [MH]⁺ = 211  12/103

83% [MH]⁺ = 197  12/106

30% [MH]⁺ = 294  12/107

46% [MH]⁺ = 294  12/109

33% [MH]⁺ = 212  12/110

67% [MH]⁺ = 311

Preparative Example 13

Step A

A degassed suspension of commercially available6-Bromo-4H-benzo[1,4]oxazin-3-one (8.39 g), Zn(CN)₂ (3.46 g) andPd(PPh₃)₄ (2.13 g) in DMF (70 mL) was stirred in a oil bath (80° C.)overnight. The mixture was cooled to room temperature and then pouredinto water (500 mL). The precipitate was collected by suction, airdried, washed with pentane, dissolved in CH₂Cl₂/MeOH (1:1), filteredthrough an silica pad and concentrated to yield a yellow solid (5.68 g,89%). [MH]⁺=175.

Step B

To an ice cooled solution of the title compound from Step A above (5.6g), di-tert-butyl dicarbonate (14.06 g) and NiCl₂.6H₂O (1.53 g) in MeOH,NaBH₄ (8.51 g) was added in portions. The mixture was vigorously stirredfor 1 h at 0° C. and 1 h at room temperature. After the addition ofdiethylenetriamine (3.5 mL) the mixture was concentrated, diluted withEtOAc, washed subsequently with 1N HCl, saturated aqueous NaHCO₃ andsaturated aqueous NaCl, dried (MgSO₄), concentrated to afford the titlecompound as an off-white solid (7.91 g, 88%). [M+Na]⁺=397.

Step C

The title compound from Step B above (7.91 g) was dissolved in a 4Msolution of HCl in 1,4-dioxane (120 mL), stirred for 14 h, concentrated,suspended in Et₂O, filtered and dried to afford the title compound as anoff-white solid (5.81 g, 96%). [M—NH₃Cl]⁺=162.

Preparative Example 14

Step A

A solution of commercially available7-cyano-1,2,3,4-tetrahydroisoquinoline (2.75 g), K₂CO₃ (3.60 g) andbenzylchloroformate (2.7 mL) in THF/H₂O was stirred overnight and thenconcentrated. The residue was diluted with EtOAc, washed with 10%aqueous citric acid, saturated aqueous NaHCO₃ and brine, dried (MgSO₄)and concentrated. The residue was dissolved in MeOH (100 mL) anddi-tert-butyl dicarbonate (7.60 g) and NiCl₂.6H₂O (400 mg) was added.The solution was cooled to 0° C. and NaBH₄ (2.60 g) was added inportions. The mixture was allowed to reach room temperature and thenvigorously stirred overnight. After the addition of diethylenetriamine(2 mL) the mixture was concentrated, diluted with EtOAc, washedsubsequently with 10% aqueous citric acid, saturated aqueous NaHCO₃ andsaturated aqueous NaCl, dried (MgSO₄), concentrated and purified bychromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as acolorless oil (1.81 g, 26%). [MH]⁺=397.

Preparative Example 15

Step A

A mixture of the title compound from the Preparative Example 14 (1.81 g)and Pd/C (10 wt %, 200 mg) in EtOH (50 mL) was hydrogenated atatmospheric pressure overnight, filtered and concentrated to a volume of˜20 mL. 3,4-Diethoxy-3-cyclobutene-1,2-dione (0.68 mL) and NEt₃ (0.5 mL)were added and the mixture was heated to reflux for 4 h. Concentrationand purification by chromatography (silica, cyclohexane/EtOAc) affordeda slowly crystallizing colorless oil. This oil was dissolved in EtOH (20mL) and a 28% solution of NH₃ in H₂O (100 mL) was added. The mixture wasstirred for 3 h, concentrated, slurried in H₂O, filtered and dried underreduced pressure. The remaining residue was dissolved in a 4M solutionof HCl in 1,4-dioxane (20 mL), stirred for 14 h, concentrated, suspendedin Et₂O, filtered and dried to afford the title compound as an off-whitesolid (1.08 g, 92%). [M—Cl]⁺=258.

Preparative Example 16

Step A

The title compound from step A above (1 g), ethyl cyanoacetate (1.44 g),acetic acid (70 μL) and ammonium acetate (30 mg) in toluene were heatedto reflux in presence of a Dean-Stark overnight. After concentration ofthe mixture, the product was used without further purification.[MH]⁺=240.

Preparative Examples 17/4 to 17/23

Following similar procedures as described in the Preparative Examples 16except using the ketones indicated in Table I.6 below, the followingcompounds were prepared.

TABLE I.6 Ex. # Ketone product yield 17/4 

n.d. [MH]⁺ = n.d. 17/6 

n.d. [MH]⁺ = n.d. 17/11

n.d. [MH]⁺ = 216 17/16

n.d. [MH]⁺ = 223 17/18

n.d. [MH]⁺ = n.d. 17/19

n.d. [MH]⁺ = n.d. 17/22

n.d. [MH]⁺ = 237 17/23

n.d. [MH]⁺ = 237

Preparative Example 18

Step A

A mixture of the title compound from the Preparative Example 16 (0.5 g)and sulfur (86 mg) in MeOH (5 mL) were heated at 50° C. Diethylamine(135 μL) was added slowly and the mixture was stirred at 50° C. for 2 h.After concentration of the mixture, a purification by chromatography(silica cyclohexane/EtOAc 9/1) afforded a orange solid (44% for 2steps). [MH]⁺=258.

Preparative Examples 18/4 to 18/24

Following similar procedures as described in the Preparative Examples 18except using the adduct indicated in Table I.7 below, the followingcompounds were prepared.

TABLE I.7 Ex. # Adduct product yield 18/4 

39% (2 steps) [MH]⁺ = 250 18/6 

76% (2 steps) [MH]⁺ = 286 18/11

49% (2 steps) [MH]⁺ = 258 18/16

n.d. [MH]⁺ = 255 18/18

n.d. [MH]⁺ = n.d. 18/19

n.d. [MH]⁺ = n.d. 18/20

n.d. [MH]⁺ = 290 18/23

16% (2 steps). [MH]⁺ = 269 18/24

25% (2 steps). [MH]⁺ = 269

Preparative Example 92

Step A

To a solution of commercially available 2-amino-4-bromophenol (1.00 g)in THF (10 mL) a solution of 2-chloropyridine-3-carbonyl chloride (0.91g) in THF (5 mL) was added at room temperature and the mixture wasrefluxed for 1 h. The mixture was cooled to room temperature and within2 d needles precipitated out which were filtered of to give 0.43 g ofthe title compound. To the filtrate water was added (100 ml) and theformed precipitate was filtered off and evaporated to dryness to affordadditional 0.91 g of the title compound. (total yield 1.34 g, 77%).[MH]⁺=327/329.

Step B

To a solution of the title compound from step A above (0.91 g) in DMF(30 ml) sodium methoxide (209 mg) was added in one portion and themixture was refluxed for 3 h, cooled to room temperature overnight andrefluxed again for 8 h. The mixture was concentrated to dryness anddissolved in EtOAc. The organic layer was washed with saturated NaHCO₃and the formed precipitate was filtered off and dried to afford thetitle compound (0.42 g). The organic layer was dried (MgSO₄) andconcentrated to afford additional 0.23 g of the title compound. (totalyield 0.65 g, 81%). [MH]⁺=291/293.

Preparative Example 93

Step A

A solution of 4-bromo-2-methylphenol was stirred in 30% aqueous HNO₃ atabout 5° C. for 30 min, filtered and used immediately without furtherpurification.

Preparative Example 94

Step A

A solution of 6-bromo-4H-benzo[1,4]oxazin-3-one (1.5 g),3-cyanophenylboronic acid (1.17 g), Pd(OAc)₂ (81 mg), dppf (221 mg) indegassed dry DMF (˜60 mL) and NEt₃ (˜1 mL) was stirred overnight underArgon at 100° C., evaporated and diluted with ethyl acetate, washed with1N HCl and brine, dried and absorbed on silica. Flash chromatography(cyclohexane/ethyl acetate 8:2 to 6:4) afforded the title compound (163mg, 9%) as a colorless solid. [MNa]⁺=251.

Preparative Example 95

Step A

A suspension of the title compound from Preparative Example 98 (48 mg),cyanamide (80 mg), NEt₃ (20 μL) in dry MeOH (10 mL) was stirred at 60°C. overnight, evaporated, absorbed on silica and purified by flashchromatography (cyclohexane/ethyl acetate 6:4) to give the titlecompound (41 mg) as a colorless solid. [MNa]⁺=325.

Preparative Example 96

Step A

A suspension of the title compound from Preparative Example 98 (81 mg),HONH₂.HCl (60 mg), NEt₃ (100 μL) in dry MeOH (10 mL) was stirred at roomtemperature overnight, evaporated, diluted with EtOAc and washed withwater and brine, dried and evaporated to give the title compound (90 mg,quant.) as a colourless solid. [MNa]⁺=316.

Preparative Example 97

Step A

A suspension of 6-amino-2,3-difluorophenol (1.0 g), K₂CO₃ (3 g),bromoacetyl chloride (750 μL) and a catalytic amount of TBAI in dryacetonitrile was stirred at reflux overnight, evaporated and dilutedwith ethyl acetate, washed with 1N HCl, brine and a saturated solutionof NaHCO₃, dried and evaporated to give the title compound (1.1 g, 86%)as a brown solid [MH]⁺=186.

Step B

The title compound of Step A above (1.1 g) was dissolved in acetic acidand bromine (1 mL) was added. The solution was stirred at roomtemperature overnight, then additional bromine (1 mL) was added and thetemperature was elevated to 40° C. for 3 h. The solution was evaporatedand diluted with ethyl acetate, washed with a aqueous solution of sodiumsulfite, brine and a saturated solution of sodium hydrogen carbonate,dried, absorbed on silica and purified by flash chromatography(cyclohexane/ethyl acetate 8:2 to 7:3) to give the 5-bromo-isomer (787mg, 50%) and 6-bromo-isomer (567 mg, 36%) as off-white solids.[MH]⁺=264/266.

Preparative Example 98

Step A

A suspension of the title compound from Preparative Example 13, Step B(380 mg) and Lawesson's reagent (660 mg) in dry THF was stirred at roomtemperature for 4 h, evaporated and diluted with ethyl acetate, washedwith water and purified by flash chromatography (cyclohexane/ethylacetate 85:15 to 8:2) to afford the title compound (312 mg, 78%) as acolourless solid. [MNa]⁺=317.

Preparative Example 99

Step A

A suspension of 2-amino-5-fluorophenol (1.0 g), catalytic amounts ofTBAI and K₂CO₃ (3.2 g) in dry CH₃CN (40 mL) was added slowly bromoacetylchloride (790 μL) at room temperature and then heated to reflux for 4 h,evaporated and diluted with 1N hydrochloric acid, filtered and dried toafford the title compound (1.21 g, 92%) as a brown solid. [MH]⁺=168.

Step B

To a suspension of the title compound from Step A above (1.21 g) informic acid (20 mL) and added bromine (850 μL) and stirred for 4 h,evaporated and redissolved in ethyl acetate, washed with water andabsorbed on silica. Purification by flash chromatography(cyclohexane/ethyl acetate 8:2 to 7:3) to afford the title compound (382mg, 21%) as an off-white solid. [MH]⁺=246/248.

Preparative Example 99/1 and 99/2

Following similar procedures as described in the Preparative Examples99, except using the educt indicated in Table I.7 below, the followingcompounds were prepared.

TABLE I.7 Ex. # Bromide product yield 99/1

n.d. [MH]⁺ = 246/248 99/2

40% [MH]⁺ = 242/244

Preparative Example 100

Step A

A suspension of 4-bromo-2-fluoro-6-nitrophenol (6.91 g),methylbromoacetate (3.3 mL), catalytic amounts of TBAI and K₂CO₃ (7.4 g)in dry DMF (100 mL) was stirred at 0° C. and allowed to reach roomtemperature for 2 d, evaporated and redissolved in ethyl acetate, washedwith water, 1N hydrochloric acid, saturated aqueous NaHCO₃ and brine,dried and evaporated to give crude intermediate, which was absorbed onsilica and purified by flash chromatography (cyclohexane/ethyl acetate9:1 to 8:2) to afford the title compound (8.2 g, 91%) as a colourlesssolid. [MH]⁺=308/310.

Step B

A suspension of the title compound from Step A above (1.35 g) and tin(1.3 g; 10-40 mesh) in methanol (2 mL) and concentrated hydrochloricacid (10 mL) was heated to reflux for 2 h, cooled, evaporated andsuspended in water, filtered and dried to afford the title compound (985mg, 91%) as colourless solid. [MH]⁺=246/48.

Preparative Example 100/1

Following similar procedures as described in the Preparative Examples100, except using the educt indicated in Table I.8 below, the followingcompounds were prepared.

TABLE I.8 Ex. # Bromide product yield 100/1

n.d. [MH]⁺ = 242/244

Preparative Example 101/4 to 101/4

Following similar procedures as described in the Preparative Examples13, Step A, except using the bromide indicated in Table I.9 below, thefollowing compounds were prepared.

TABLE I.9 Ex. # Bromide product yield 101/1

93% [MH]⁺ = 193 101/2

n.d. [MH]⁺ = 193 101/3

n.d. [MH]⁺ = 189 101/4

n.d. [MH]⁺ = 238

Preparative Example 102/1 to 102/9

Following similar procedures as described in the Preparative Examples13, Step B, except using the cyanide indicated in Table I.10 below, thefollowing compounds were prepared.

TABLE I.10 Ex. # Cyanide product yield 102/1

56% [MNa]⁺ = 319 102/2

28% (two steps) [MNa]⁺ = 319 102/3

32% (3 steps) [MNa]⁺ = 319 102/4

64% [MNa]⁺ = 337 102/5

47% (two steps) [MNa]⁺ = 337 102/6

83% [MNa]⁺ = 377 102/7

61% [MNa]⁺ = 315 102/8

41% (two steps) [MNa]⁺ = 315 102/9

36% [MH]⁺ = 225

Preparative Example 103/1 to 103/12

Following similar procedures as described in the Preparative Examples13, Step C, except using the educt indicated in Table I.11 below, thefollowing compounds were prepared.

TABLE I.11 Ex. # Educt product yield 103/1

quant. [M − NH₃Cl]⁺ = 180 103/2

quant. [M − NH₃Cl]⁺ = 180 103/3

quant. [M − Cl]⁺ = 194 103/4

quant. [M − NH₃Cl]⁺ = 180 103/5

quant. [M − Cl]⁺ = 215 103/6

quant. [M − Cl]⁺ = 215 103/7

quant. [M − Cl]⁺ = 194 103/8

quant. [M − Cl]⁺ = 200 103/9

quant. [M − Cl]⁺ = 255  103/10

quant. [M − Cl]⁺ = 193  103/11

n.d. [M − NH₃Cl]⁺ = 193  103/12

quant. [M − NH₃Cl]⁺ = 225

Preparative Example 104

Step A

A suspension of the title compound from Preparative Example 99/1 (˜1.3g) and CuCN (820 mg) in degassed NMP was stirred in a closed vial undermicrowave irradiation at 180° C. for 10 h, evaporated and redissolved inethyl acetate, washed with water, 1N hydrochloric acid, saturatedaqueous NaHCO₃ and brine, dried and evaporated to give crudeintermediate, which was used without further purification. [MH]⁺=193.

Preparative Example 104/1 to 104/3

Following similar procedures as described in the Preparative Examples104, except using the bromide indicated in Table I.12 below, thefollowing compounds were prepared.

TABLE I.12 Ex. # Bromide product yield 104/1

n.d. [MH]⁺ = 211 104/2

55% [MH]⁺ = 211 104/3

91% [MH]⁺ = 189

Preparative Example 105

Step A

Ethyl acetamidocyanoacetate (1 g) and Lawesson's reagent (1.2 g) wereplaced in benzene and refluxed for 24 h in presence of a Dean-Starkapparatus. After evaporation, a purification by flash chromatography(dichloromethane/methanol 98/2) afforded the title product (0.6 g, 30%)as a yellow oil. [MH]⁺=187.

Preparative Example 110

Step A

To a solution of Carbamimidoyl-acetic acid ethyl ester (0.5 g) in ethylacetate (6 mL) was added triethylamine (0.5 mL) and mixture was stirredat 5° C. Than 3-Bromo-butan-2-one (0.4 mL) was added under a nitrogenatmosphere and the mixture was refluxed for 1 h. The reaction mixturewas then filtered through a medium porosity fitted glass funnelcontaining a thin layer of silica gel. The filtrate was washed with 100mL of ethyl acetate and the combined washes were then evaporated underreduced pressure to give (0.25 g, 35%) of2-Amino-4,5-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester [MH]⁺=183.

Step B

To a round bottom flask containing a stir bar was added NaH (65 mg; 60%in oil) and the mixture was placed under a nitrogen atmosphere. To thesolid was then added of pyrole product (0.25 g) dissolved in 4 ml ofanhydrous dimethylformamide and the mixture was stirred at 0° C. for 30minutes and then 30 minutes at room temperature. To the mixture was thenadded methyl iodide (0.23 mL) at 0° C. and the mixture was stirred for30 minutes. To the mixture was then added 50 ml of 10% aqueous ammoniumacetate solution and mixture acidified to pH ˜7 using acetic acid. Theaqueous layer was then extracted with 100 mL of diethyl ether. Theorganic layer was separated, dried over MgSO4, filtered and the volatilecomponents removed under reduced pressure to give the desired product(150 mg, 55%). [MH]⁺=197.

Preparative Example 111

Step A

A mixture of 5-amino-3-methylisoxazole-4-carboxamide (283 mg), diethyloxalate (1168 mg) and NaOEt (3 mL, 21% wt in EtOH) in EtOH (17 mL) washeated to reflux. The reaction mixture was concentrated under reducedpressure and the residue was dissolved in water (˜20 ml). The resultingsolution was acidified with AcOH and the separated solid was collected.The solid was dried to afford desired compound (307 mg, 69%). [MH]⁺=224.

Preparative Example 111/1

Following similar procedures as described in the Preparative Examples111, except using the bromide indicated in Table I.14 below, thefollowing compounds were prepared.

TABLE I.14 Ex. # Amine product yield 111/1

80% [MH]⁺ = 209

Example 1

Step A

To a solution of the title compound from Preparative Example 11 above(55 mg), EDCI (108 mg) and HOAt (46 mg) in DMF (10 mL) were addedN-methylmorpholine (100 μL) and the title compound from the PreparativeExample 13 (72 mg). The mixture was stirred overnight and thenconcentrated. The remaining residue was suspended in 10% aqueous citricacid and the residue was filtered to afford the title compound as an offwhite solid (65 mg, 65%). [MH]⁺=357.

Examples 2/1-2/548

Following similar procedures as described in the Examples 1, exceptusing the amines and acids indicated in Table II.1 below, the followingcompounds were prepared.

TABLE II.1 Ex. # amine, acid 2/1

2/2

2/3

2/4

2/5

2/6

2/7

2/8

2/9

2/10

2/11

2/12

2/13

2/14

2/15

2/16

2/17

2/18

2/19

2/20

2/21

2/22

2/23

2/26

2/27

2/28

2/31

2/32

2/35

2/37

2/38

2/39

2/40

2/41

2/42

2/43

2/44

2/45

2/46

2/47

2/48

2/49

2/50

2/51

2/53

2/54

2/55

2/56

2/57

2/58

2/59

2/60

2/61

2/62

2/63

2/64

2/65

2/66

2/68

2/69

2/70

2/71

2/72

2/73

2/74

2/75

2/76

2/77

2/78

2/79

2/80

2/81

2/82

2/83

2/84

2/85

2/86

2/87

2/88

2/91

2/92

2/93

2/96

2/97

2/98

2/99

2/100

2/101

2/102

2/105

2/106

2/109

2/110

2/111

2/112

2/115

2/116

2/123

2/124

2/127

2/128

2/133

2/134

2/135

2/136

2/137

2/138

2/139

2/140

2/141

2/142

2/147

2/148

2/149

2/150

2/151

2/154

2/155

2/156

2/157

2/158

2/159

2/160

2/161

2/162

2/163

2/164

2/165

2/179

2/180

2/181

2/182

2/183

2/184

2/185

2/186

2/189

2/190

2/191

2/192

2/193

2/194

2/195

2/196

2/197

2/198

2/199

2/200

2/201

2/202

2/203

2/204

2/205

2/206

2/207

2/213

2/214

2/215

2/216

2/217

2/220

2/221

2/222

2/226

2/227

2/228

2/229

2/233

2/234

2/235

2/241

2/242

2/243

2/244

2/247

2/248

2/265

2/271

2/273

2/275

2/276

2/277

2/278

2/279

2/280

2/281

2/282

2/283

2/284

2/285

2/286

2/287

2/288

2/373

2/374

2/375

2/378

2/379

2/380

2/381

2/548

Ex. # product yield 2/1

77% [MH]⁺ = 351 2/2

57% [MH]⁺ = 365 2/3

80% [MH]⁺ = 365 2/4

76% [MH]⁺ = 351 2/5

25% [MH]⁺ = 324 2/6

87% [MH]⁺ = 360 2/7

71% [MH]⁺ = 322 2/8

74% [MH]⁺ = 365 2/9

98% [MH]⁺ = 371 2/10

90% [MH]⁺ = 450 2/11

67% [MH]⁺ = 449/451 2/12

72% [MH]⁺ = 365 2/13

82% [MH]⁺ = 444 2/14

83% [MH]⁺ = 458 2/15

83% [MH]⁺ = 418 2/16

73% [MH]⁺ = 432 2/17

79% [MH]⁺ = 426 2/18

65% [MH]⁺ = 324 2/19

73% [MH]⁺ = 346 2/20

n.d. [MH]⁺ = 357 2/21

77% [MH]⁺ = 429/431 2/22

78% [MH]⁺ = 443 2/23

62% [MH]⁺ = 369 2/26

63% [MH]⁺ = 385 2/27

93% [MH]⁺ = 385 2/28

88% [MH]⁺ = 443 2/31

10% [MH]⁺ = 366 2/32

13% [MH]⁺ = 366 2/35

67% [MH]⁺ = 385 2/37

55% [MH]⁺ = 385 2/38

87% [MH]⁺ = 385 2/39

73% [MH]⁺ = 419/431 2/40

80% [MH]⁺ = 429/431 2/41

79% [MH]⁺ = 376 2/42

71% [MH]⁺ = 477 2/43

12% [MH]⁺ = 419 2/44

12% [MH]⁺ = 419 2/45

54% [MH]⁺ = 409 2/46

63% [MH]⁺ = 385 2/47

86% [MH]⁺ = 352 2/48

79% [MH]⁺ = 352 2/49

11% [MH]⁺ = 439 2/50

33% [MH]⁺ = 365 2/51

15% [MH]⁺ = 518 2/53

85% [MH]⁺ = 413 2/54

64% [MH]⁺ = 413 2/55

15% [MH]⁺ = 355 2/56

85% [MH]⁺ = 510 2/57

26% [MH]⁺ = 396 2/58

48% [MH]⁺ = 414 2/59

4% [MH]⁺ = 428 2/60

39% [MH]⁺ = 408 2/61

24% [MH]⁺ = 484 2/62

21% [MH]⁺ = 490 2/63

55% [MH]⁺ = 455 2/64

79% [MH]⁺ = 411 2/65

66% [MH]⁺ = 411 2/66

88% [MH]⁺ = 464 2/68

40% [MH]⁺ = 431 2/69

76% [MH]⁺ = 377 2/70

85% [MH]⁺ = 379 2/71

75% [MH]⁺ = 381 2/72

85% [MH]⁺ = 368 2/73

85% [MH]⁺ = 446 2/74

67% [MH]⁺ = 369 2/75

78% [MH]⁺ = 448 2/76

86% [MH]⁺ = 387 2/77

81% [MH]⁺ = 466 2/78

76% [MH]⁺ = 393 2/79

87% [MH]⁺ = 472 2/80

68% [MH]⁺ = 407 2/81

80% [MH]⁺ = 486 2/82

85% [MH]⁺ = 448 2/83

91% [MH]⁺ = 492 2/84

>99% [MH]⁺ = 451 2/85

90% [MH]⁺ = 530 2/86

52% [MH]⁺ = 425 2/87

37% [MH]⁺ = 504 2/88

86% [MH]⁺ = 413 2/91

69% [MH]⁺ = 422 2/92

89% [MH]⁺ = 568 2/93

95% [MH]⁺ = 484 2/96

70% [MH]⁺ = 533 2/97

35% [MH]⁺ = 423 2/98

87% [MH]⁺ = 502 2/99

5% [MH]⁺ = 512 2/100

18% [MH]⁺ = 433 2/101

71% [MH]⁺ = 467 2/102

quant. [MH]⁺ = 547 2/105

quant. [MH]⁺ = 447 2/106

quant. [MH]⁺ = 526 2/109

quant. [MH]⁺ = 463 2/110

quant. [MH]⁺ = 542 2/111

69% [MH]⁺ = 355 2/112

76% [MH]⁺ = 434 2/115

73% [MH]⁺ = 434 2/116

50% [MH]⁺ = 513 2/123

80% [MH]⁺ = 447 2/124

88% [MH]⁺ = 526 2/127

93% [MH]⁺ = 399 2/128

97% [MH]⁺ = 478 2/133

n.d. [MH]⁺ = 341 2/134

13% [MH]⁺ = 451 2/135

41% [MH]⁺ = 357 2/136

9% [MH]⁺ = 372 2/137

96% [MH]⁺ = 417 2/138

88% [MH]⁺ = 509 2/139

99% [MH]⁺ = 588 2/140

87% [MH]⁺ = 399 2/141

72% [MH]⁺ = 478 2/142

89% [MH]⁺ = 464 2/147

72% [MH]⁺ = 443 2/148

n.d [MH]⁺ = 522 2/149

16% [MH]⁺ = 575 2/150

6% [MH]⁺ = 434 2/151

19% [MH]⁺ = 513 2/154

21% [MH]⁺ = 352 2/155

55% [MH]⁺ = 431 2/156

79% [MH]⁺ = 414 2/157

85% [MH]⁺ = 428 2/158

54% [MH]⁺ = 493 2/159

32% [MH]⁺ = 521 2/160

50% [MH]⁺ = 442 2/161

85% [MH]⁺ = 521/523 2/162

n.d. [MH]⁺ = n.d. 2/163

84% [MH]⁺ = 457 2/164

n.d. [MH]⁺ = 567 2/165

70% [MH]⁺ = 561 2/179

20% [MH]⁺ = 372 2/180

24% [MH]⁺ = 451 2/181

20% [MH]⁺ = 372 2/182

70% [MH]⁺ = 561 2/183

97% [MH]⁺ = 442 2/184

2% [MH]⁺ = 401 2/185

46% [MH]⁺ = 435 2/186

41% [MH]⁺ = 514 2/189

80% [MH]⁺ = 471 2/190

45% [MH]⁺ = 442 2/191

71% [MH]⁺ = 446 2/192

53% [MH]⁺ = 369 2/193

38% [MH]⁺ = 387 2/194

94% [MH]⁺ = 403 2/195

78% [MH]⁺ = 352 2/196

86% [MH]⁺ = 370 2/197

81% [MH]⁺ = 386 2/198

62% [MH]⁺ = 367 2/199

63% [MH]⁺ = 401 2/200

73% [MH]⁺ = 369 2/201

88% [MH]⁺ = 403 2/202

79% [MH]⁺ = 369 2/203

90% [MH]⁺ = 387 2/204

89% [MH]⁺ = 896 2/205

59% [MH]⁺ = 351 2/206

91% [MH]⁺ = 552 2/207

65% [MH]⁺ = 516 2/213

72% [MH]⁺ = 387 2/214

95% [MH]⁺ = 421 2/215

n.d. [MH]⁺ = 513/515/517 2/216

89% [MH]⁺ = 387 2/217

74% [MH]⁺ = 421 2/220

n.d. [MH]⁺ = 366 2/221

n.d. [MH]⁺ = 409 2/222

80% [MH]⁺ = 528/530 2/226

59% [MH]⁺ = 443 2/227

65% [MH]⁺ = 522 2/228

34% [MH]⁺ = 589 2/229

70% [MH]⁺ = 428 2/233

77% [MH]⁺ = 442 2/234

57% [MH]⁺ = 456 2/235

90% [MH]⁺ = 466 2/241

46% [MH]⁺ = 391 2/242

53% [MH]⁺ = 470 2/243

63% [MH]⁺ = 417 2/244

63% [MH]⁺ = 496 2/247

31% [MH]⁺ = 387 2/248

3% [MH]⁺ = 446 2/265

34% (5 steps) [MH]⁺ = 440 2/271

10% [MH]⁺ = 508 2/273

86% [MH]⁺ = 461 2/275

88% [MH]⁺ = 400 2/276

87% [MH]⁺ = 399 2/277

81% [MH]⁺ = 399 2/278

62% [MH]⁺ = 365 2/279

23% [MH]⁺ = 410 2/280

19% [MH]⁺ = 376 2/281

11% [MH]⁺ = 463/465 2/282

5% [MH]⁺ = 419 2/283

n.d. [MH]⁺ = 461 2/284

n.d. [MH]⁺ = 461 2/285

36% [MH]⁺ = 414 2/286

78% [MH]⁺ = 428 2/287

36% [MH]⁺ = 468 2/288

9% [MH]⁺ = 276 2/373

46% [MH]⁺ = 475 2/374

32% [MH]⁺ = 357 2/375

49% [MH]⁺ = 489 2/378

92% [MH]⁺ = 454 2/379

9% [MH]⁺ = 454 2/380

quant. [MH]⁺ = 475 2/381

quant. [MH]⁺ = 492 2/548

41% [MH]⁺ = 436

Example 3

Step A

To a degassed suspension of the title compound from Example 2/21 above(100 mg) in MeOH (5 mL) were added NEt₃ (70 μL) palladium acetate (2 mg)and dppf (4.5 mg). The mixture was stirred overnight at 70° C. under COatmosphere (7 bar) and then concentrated. The remaining residue waspurified by chromatography (silica, chloroform/MeOH) to afford the titlecompound as off white solid (70 mg, 74%). [MH]⁺=409.

Step B

To a solution of the title compound from Step A above (65 mg) in THF (3mL) was added 1M aqueous LiOH (450 μL). The resulting mixture wasstirred at room temperature overnight, concentrated and suspended in 1Maqueous HCl. The residue was filtered off and used without furtherpurification (36 mg, 57%). [MH]⁺=395.

Examples 4/1-4/20

Following a similar procedure as described in Example 3 step B, exceptusing the ester indicated in Table II.2 below, the following compoundswere prepared.

TABLE II.2 Ex. # Ester 4/1

4/2

4/3

4/5

4/6

4/7

4/8

4/12

4/13

4/20

Ex. # product Yield 4/1

66% [MH]⁺ = 415 4/2

73% [MH]⁺ = 415 4/3

70% [MH]⁺ = 554 4/5

nd. [MH]⁺ = 494 4/6

82% [MH]⁺ = 415 4/7

73% [MH]⁺ = 429 4/8

92% [MH]⁺ = 443 4/12

81% [MH]⁺ = 429 4/13

36% [MH]⁺ = 429 4/20

70% [MH]⁺ = 447

Example 5

Step A

The title compound from the Example 2/57 (77 mg) and Pd/C (10%; 75 mg)were suspended in THF/MeOH and AcOH (100 μL) and hydrogenated atatmospheric pressure for 5 h, filtered over celite and evaporated toafford the title compound as a yellow solid. [MH]⁺=366.

Example 6

Step A

To a degassed suspension of the title compound from Example 2/42 above(120 mg) in DMF (2 mL) were added 17 mg Pd(PPh₃)₄, 34 mg commerciallyavailable phenylboronic acid and 2M aqueous Na₂CO₃ (0.5 mL). Theresulting mixture was stirred at 130° C. (3 h) in a microwave oven for30 min and than concentrated. The remaining residue was purified bychromatography (silica, chloroform/MeOH) to afford the title compound asoff-white solid (11 mg, 22%). [MH]⁺=427.

Examples 7/1

Following a similar procedure as described in the Example 6, exceptusing the aryl halogenide and boronic acid indicated in Table II.3below, the following compounds were prepared.

TABLE II.3 Ex. # aryl halogenide, boronic acid product yield 7/1

25% [MH]⁺ = 433

Example 8

Step A

To a degassed suspension of the title compound from Example 2/42 above(70 mg) and CuI in DMF (2 mL) were added 17 mg Pd(PPh₃)₂Cl₂ and 16 mgcommercially available trimethylsilyl acetylen. The resulting mixturewas stirred at 120° C. (3 h) in a microwave oven for 20 min and thanconcentrated. The remaining residue was dissolved in H₂O/ethyl acetate,organic layer was dried (MgSO₄) and concentrated. The remaining residuewas dissolved in MeOH K₂CO₃ (25 mg) was added and the mixture wasstirred for 2 h, concentrated and purified by chromatography (silica,chloroform/MeOH) to afford the title compound as off white solid (2 mg,3%). [MH]⁺=375.

Example 8/1

Following a similar procedure as described in the Example 8, exceptusing the aryl halogenide and acetylene indicated in Table II.4 below,the following compounds were prepared.

TABLE II.4 Ex. # aryl halogenide, acetylene product yield 8/1

10% [MH]⁺ = 451

Example 9

Step A

A mixture of the title compound from the Example 2/21 (150 mg), Zn(CN)₂(31 mg) and Pd(PPh₃)₄ (20 mg) in dry DMF (3 mL) was degassed and heatedat 85° C. under an argon atmosphere overnight. The mixture wasconcentrated, diluted with 10% aqueous citric acid, filtered and theremaining residue was slurried in methanol, filtered and dried to affordthe title compound as a colorless solid (103 mg, 78%). [MH]⁺=376.

Examples 10/1-10/2

Following a similar procedure as described in the Example 9, exceptusing the aryl halogenide indicated in Table II.5 below, the followingcompounds were prepared.

TABLE II.5 Ex. # aryl halogenide 10/1

10/2

Ex. # product yield 10/1

89% [MH]⁺ = 376 10/2

n.d. [MH]⁺ = 468

Example 11

Step A

In a sealed vial was a mixture of the title compound from the Example 9(43.3 mg), dibutyltin oxide (12 mg) and azidotrimethylsilane (400 μL) indry toluene (10 mL) under an argon atmosphere heated at 170° C. usingmicrowave irradiation for 13 h. The reaction mixture was absorbed onsilica gel and purified by chromatography (silica, CH₂Cl₂/MeOH 9:1 to4:1) and the product containing fractions further purified by thin layerchromatography (CH₂Cl₂/MeOH 4:1) to give the title compound as anoff-white solid (6.1 mg, 14%). [MH]⁺=419.

Example 12

Step A

The title compound from the Example 9 (28.2 mg) and K₂CO₃ (21 mg) weresuspended in DMSO (1 mL) and aqueous hydrogen peroxide (35%, 100 μL) wasadded. The reaction mixture was stirred for 3 h and diluted with 10%aqueous citric acid, filtered and dried to afford the title compound asa colorless solid (34.9 mg, quant.). [MH]⁺=394.

Examples 13/1-13/3

Following a similar procedure as described in Example 12, except usingthe aryl cyanide indicated in Table II.6 below, the following compoundswere prepared.

TABLE II.6 Ex. # aryl halogenide 13/1

13/2

13/3

Ex. # product yield 13/1

87% [MH]⁺ = 394 13/2

41% [MH]⁺ = 473 13/3

60% [MH]⁺ = 394

Example 14

Step A

To an ice cooled solution of the title compound from the Example 9 (980mg) in dry MeOH (20 mL) were added di-tert-butyl dicarbonate (1.5 g) andNiCl₂.6H₂O (190 mg), followed by the careful portionwise addition ofNaBH₄ (600 mg). The resulting black mixture was stirred for 20 min at0-5° C. (ice bath), then the ice bath was removed and stirring at roomtemperature was continued overnight. Then diethylenetriamine was addedand the mixture was concentrated to dryness. The remaining residue wassuspended in EtOAc washed subsequently with 10% aqueous citric acid,saturated aqueous NaHCO₃ and saturated aqueous NaCl, dried (MgSO₄),filtered, concentrated and purified by chromatography (silica,cyclohexane/EtOAc 2:8 to 0:1) to afford the title compound as acolorless solid (262 mg, 21%). [MH]⁺=480.

Example 15

Step A

To the title compound from the Example 14 (258 mg) was added a 4Msolution of HCl in 1,4-dioxane (10 mL). The reaction mixture was stirredat room temperature with temporary sonification for 5 h and concentratedto afford the title compound (240 mg, >99%). [M—Cl]⁺=380.

Example 16

Step A

The title compound from the Example 2/88 (24.5 mg), HONH₂.HCl (39 mg),NaOAc (50 mg) and 3 drops aniline were stirred in MeOH/H₂O (10 mL; 1:1)at 80° C. for 2 d. The reaction mixture was concentrated, diluted withwater and filtered to afford the title compound (23 mg, 91%) as anoff-white solid. [MH]⁺=428.

Example 17

Step A

The title compound from the Example 15 (29 mg), succinic anhydride (8mg) and pyridine (80 μL) were stirred in CH₃CN at 50° C. overnight,concentrated, diluted with 10% aqueous citric acid and filtered toafford the title compound (27 mg, 81%) as an off-white solid. [MH]⁺=480.

Example 19

Step A

To DMF (5 mL) was added 2M oxalylchloride in dichloromethane (150 μL) at0° C. Then a solution of the title compound from Example 2/156 (112 mg)in DMF (2 mL) was added and the mixture was stirred for 6 h at 0° C.After adding pyridine (150 μL) the mixture was stirred for additional 2h at room temperature. The mixture was concentrated to afford the titlecompound after chromatography (chloroform/methanol=9:1; 19 mg, 18%).[MH]⁺=396.

Example 20a to Example 20c

Step A

The title compound from example 2/28 (255 mg) was dissolved in dry THF(40 mL) and then a large excess of LiBH₄ was added and the mixture wasstirred for 1 week with sonification for some time, evaporated, adjustedto pH ˜8 with aq. NH₄Cl, extracted with ethyl acetate and absorbed onsilica. Flash chromatography (CH₂Cl₂/methanol 98:2 to 85:15) affordedfirst the Example 20b (14.5 mg) as an off-white solid ([MH]⁺=429), thenExample 20c (31.4 mg) as a colourless solid ([MH]⁺=387), and finallyExample 20a (8.6 mg) as a colourless solid ([MH]⁺=401).

Example 21

Step A

The title compound from example 2/88 (100 mg) was suspended in dryTHF/MeOH (5:1) and then NaBH₄ (22 mg) was added and the mixture wasstirred for 1.5 h, acidified with 1N HCl, filtered, washed with waterand dried to afford the title compound (94 mg, 94%) as a colourlesssolid. [MH]⁺=415.

Example 23a to Example 23c

Step A

A suspension the title compound from Example 2/215 (170 mg) and CuCN (66mg) in degassed DMF was stirred in a closed vial under microwaveirradiation at 200° C. for 1 h, evaporated and redissolved in THF,washed with brine/1N hydrochloric acid (˜1:1) and brine, dried andseparated by HPLC to afford both mono-nitrile products ([MH]⁺=382) andthe di-nitrile product ([MH]⁺=407).

Example 23/1

Following a similar procedure as described in Example 23a, except usingthe educt indicated in Table II.10 below, the following compounds wereprepared.

TABLE II.10 Ex. # Educt product yield 23/1

quant. [MH]⁺ = 396

Example 24

Step A

The title compound from Example 20c (29 mg) and catalytic amounts ofDMAP were stirred in Ac₂O/pyridine (3 mL; 1:2) overnight, evaporated,coevaporated with toluene, slurried in water and filtered to afford thetitle compound (33 mg, 93%) as an off-white solid. [MH]⁺=471.

Example 25

Step A

The title compound from Example 24 (14 mg) and NaOMe (13 mg) in dry MeOHwere stirred for 1 h, evaporated, acidified with 1N hydrochloric acidand filtered to afford the title compound (9.1 mg, 71%) as a colourlesssolid. [MH]⁺=429.

Example 27

Step A

The title compound from the Example 2/88 (20 mg), MeONH₂.HCl (21 mg),NaOAc (30 mg) and 3 drops aniline were stirred in MeOH/H₂O (10 mL; 1:1)at 80° C. for 2 d. The reaction mixture was concentrated, diluted withwater and purified by HPLC to afford the title compound (7.6 mg) as acolourless solid. [MH]⁺=442.

Example 28

Step A

To a solution of9-Oxo-8,9-dihydro-1,3-dioxa-6,8-diaza-cyclopenta[a]naphthalene-7-carboxylicacid ethyl ester above (32 mg) in ethanol (1 mL) were added triethylamine (40 μL) and the title compound from the Preparative Example 13 (30mg). The mixture was heated at 180° C. in a microwave oven for 1 h andthen concentrated. The remaining residue was purified by silica gelchromatography (10% methanol in methylene chloride) to give a yellowsolid (45 mg, 95%). [MH]⁺=395.

Examples 29/1 to 29/2

Following a similar procedure as described in Example 28, except usingthe ester indicated in Table II.11 below, the following compounds wereprepared.

TABLE II.11 Ex. # Ester product Yield 29/1

64% [MH]⁺ = 498 29/2

27% [MH]⁺ = 498

Example 30

Step A

To a solution of the title compound from Example 3 above (25 mg) in DMF(2 mL) were added triethyl amine (10 μL), benzylamine (9 mg) and PyBop(38 mg). The mixture was stirred at room temperature overnight andconcentrated in vaccuo. The remaining residue was purified by silica gelchromatography (10% methanol in methylene chloride) to give a yellowsolid (10 mg, 41%). [MH]⁺=484.

Examples 31/1 to 31/4

Following a similar procedure as described in Example 30, except usingthe amine indicated in Table II.11 below, the following compounds wereprepared.

TABLE II.11 Ex. # Amine product yield 31/1

64% [MH]⁺ = 470 31/2

24% [MH]⁺ = 508 31/3

28% [MH]⁺ = 522 31/4

26% [MH]⁺ = 466

Example 32

Step A

To a 10 ml round bottom flask containing a stir bar is added 20 mg ofthe tert.-Butyl ester above, and 2 ml of 50% trifluoroacetic acid inmethylene chloride and solution stirred under closed atmosphere for 30minutes. The volatile components of the reaction mixture was thenremoved under reduced pressure to give an oil which was precipitatedfrom ether to give 8 mg (˜45% crude yield) of the free acid as a whitesolid. [MH]⁺=438.

Example 33

Step A

To a 10 ml round bottom flask containing a stir bar is added 10 mg ofthe tert.-Butyl ester above, and 2 ml of 50% trifluoroacetic acid inmethylene chloride and solution stirred under closed atmosphere for 30minutes. The volatile components of the reaction mixture was thenremoved under reduced pressure to give an oil which was precipitatedfrom ether to give 5 mg (˜56% crude yield) of the free acid as a whitesolid. [MH]⁺=438.

Example 34

Step A

To a thick walled glass vessel containing a stir bar was added of5-Fluoro-4-oxo-3,4-dihydro-quinazoline-2-carboxylic acid ethyl ester(100 mg), 120 mg of the hydrochloride salt of the6-Aminomethyl-4H-benzo[1,4]oxazin-3-one, 2 ml of ethanol and 0.15 mL oftriethylamine and mixture heated at 120° C. via microwave under closedatmosphere for 30 min. The mixture was then centrifuged and the solidwas triturated with ethanol to give 100 mg (65%) of the desired productas a white solid. [MH]⁺=369.

Example 35

Step A

To a thick walled glass vessel containing a stir bar is added 35 mg oftitle compound from Example 34 above and a solution composed of 1.5 mLof a sodium methoxide solution in methanol and 2 mL of dimethylacetamideand the mixture was heated via microwave irradiation at 180° C. for 80minutes. The volatile components of the reaction mixture were removedunder reduced pressure to give crude product. The crude was trituratedwith ethanol to give 30 mg (83%) of the desired ether product as a whitesolid. [MH]⁺=381.

Example 36

Step A

To a thick walled glass vessel containing a stir bar is added 172 mg ofthe diester above, 164 mg of the hydrochloride salt of thebenzo[1,4]oxazinone, 3 ml of ethanol and 0.2 ml of triethylamine andmixture heated at 180° C. via microwave under closed atmosphere for 1hour. The mixture was then centrifuged and the solid was repeatedlytriturated with ethanol and then methylene chloride to give 50 mg (16%yield) of the desired amide product as a white solid. [MH]⁺=409.

Examples 36/1-36/13

Following a similar procedure as described in Example 36, except usingthe amines indicated in Table II.13 below, the following compounds wereprepared.

TABLE II.13 Ex. # Amine product yield 36/1

30% [MH]⁺ = 470 36/2

40% [MH]⁺ = 470 36/3

25% [MH]⁺ = 456 36/4

25% [MH]⁺ = 499 36/5

50% [MH]⁺ = 494 36/6

50% [MH]⁺ = 494 36/7

40% [MH]⁺ = 463 36/8

30% [MH]⁺ = 463 36/10

40% [MH]⁺ = 424 36/11

50% [MH]⁺ = 424 36/12

30% [MH]⁺ = 424 36/13

35% [MH]⁺ = 424

Example 37

Step A

To a thick walled glass vessel containing a stir bar is added 69 mg of6-fluoro-4-oxo-3,4-dihydro-quinazoline-2-carboxylic acid ethyl ester, 73mg of the hydrochloride salt of the benzo[1,3,4]oxathiazine synthesizedfollowing Preparative Example 5/6, 1 mL of ethanol and 0.1 ml (0.70mmoles) of triethylamine and mixture heated at 180° C. via microwaveunder closed atmosphere for 1 h. The mixture was then centrifuged andthe solid was triturated with ethanol to give a white solid. The solidwas purified by preparative thin layer chromatography (SiO₂, 10%MeOH-methylene chloride) to give 21 mg (18% yield) of the desired6-fluoro-4-oxo-1,2,3,4-tetrahydro-quinazoline-2-carboxylic acid(2,2-dioxo-2,3-dihydro-benzo[1,3,4]oxathiazin-7-ylmethyl)-amide productas a white solid. [MH]⁺=405.

Example 38

Step A

To a thick walled glass vessel containing a stir bar is added 52 mg(0.20 mmoles) of5,6-dimethyl-4-oxo-3,4-dihydro-thieno[2,3-d]pyrimidine-2-carboxylic acidethyl ester, 65 mg of the hydrochloride salt of thebenzo[1,3,4]oxathiazine synthesized following Preparative Example 5/19,1 mL of ethanol and 0.1 ml (0.70 mmoles) of triethylamine and mixtureheated at 180° C. via microwave under closed atmosphere for 1 h. Themixture was then centrifuged and the solid was repeatedly trituratedwith ethanol and then methylene chloride to give 19 mg (22% yield) ofthe desired benzo[1,3,4]oxathiazin-7-ylmethyl)-amide product as a whitesolid. [MH]⁺=421.

Examples 39/1-39/25

Following similar procedures as described in Examples 38 except usingthe amines and the ester indicated in Table II.14 below, the followingcompounds were prepared.

TABLE II.14 Ex. # amine; ester product Yield 39/1

50% [MH]⁺ = 419 39/2

40% [MH]⁺ = 365 39/3

12% [MH]⁺ = 343 39/4

15% [MH]⁺ = 342 39/5

31% [MH]⁺ = 427 39/6

 8% [MH]⁺ = 359 39/8

22% [MH]⁺ = 369 39/9

16% [MH]⁺ = 382 39/10

25% [MH]⁺ = 370 39/11

 6% [MH]⁺ = 422 39/12

45% [MH]⁺ = 356 39/13

48% [MH]⁺ = 341 39/14

n.d. [MH]⁺ = 387 39/15

28% [MH]⁺ = 365 39/16

17% [MH]⁺ = 365 39/17

19% [MH]⁺ = 365 39/18

 5% [MH]⁺ = 385 39/19

24% [MH]⁺ = 369 39/21

60% [MH]⁺ = 381 39/22

35% [MH]⁺ = 396 39/23

27% [MH]⁺ = 448 39/24

26% [MH]⁺ = 466 39/25

15% [MH]⁺ = 444

Example 44

Step A

A mixture of (4-oxo-3,4-dihydro-quinazolin-2-yl)-acetic acid methylester (28.8 mg, 0.132 mmol),6-(aminomethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one HCl salt (34.9 mg,0.163 mmol), and triethylamine (55 μL, 40 mg, 0.40 mmol) in DMF (1 ml)was heated in a microwave at 160° C. for 5 min, then 180° C. for 1 h.Typical aqueous workup and purification provided 7.1 mg of the desiredproduct as a pale yellow solid. [MH]⁺=365.

Example 45

Step A

Utilizing the same procedure as indicated in Example 44 above exceptcoupling3-amino-4-(7-aminomethyl-3,4-dihydro-1H-isoquinolin-2-yl)-cyclobut-3-ene-1,2-dioneHCl salt with 4-Oxo-3,4-dihydro-quinazoline-2-carboxylic acid ethylester at 120° C. for 1 h provided 23.7 mg of the desired product as apale yellow solid. [MH]⁺=444.

Example 1700 Assay for Determining MMP-13 Inhibition

The typical assay for MMP-13 activity is carried out in assay buffercomprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl₂ and 0.05%Brij-35. Different concentrations of tested compounds are prepared inassay buffer in 50 μL aliquots. 10 μL of a 50 nM stock solution ofcatalytic domain of MMP-13 enzyme (produced by Alantos or commerciallyavailable from Invitek (Berlin), Cat. # 30100812) is added to thecompound solution. The mixture of enzyme and compound in assay buffer isthoroughly mixed and incubated for 10 min at room temperature. Upon thecompletion of incubation, the assay is started by addition of 40 μl of a12.5 μM stock solution of MMP-13 fluorescent substrate (Calbiochem, Cat.No. 444235). The time-dependent increase in fluorescence is measured atthe 320 nm excitation and 390 nm emission by automatic platemultireader. The IC₅₀ values are calculated from the initial reactionrates.

Example 1701 Assay for Determining MMP-3 Inhibition

The typical assay for MMP-3 activity is carried out in assay buffercomprised of 50 mM MES, pH 6.0, 10 mM CaCl₂ and 0.05% Brij-35. Differentconcentrations of tested compounds are prepared in assay buffer in 50 μLaliquots. 10 μL of a 100 nM stock solution of the catalytic domain ofMMP-3 enzyme (Biomol, Cat. No. SE-109) is added to the compoundsolution. The mixture of enzyme and compound in assay buffer isthoroughly mixed and incubated for 10 min at room temperature. Upon thecompletion of incubation, the assay is started by addition of 40 μL of a12.5 μM stock solution of NFF-3 fluorescent substrate (Calbiochem, Cat.No. 480455). The time-dependent increase in fluorescence is measured atthe 330 nm excitation and 390 nm emission by an automatic platemultireader. The IC₅₀ values are calculated from the initial reactionrates.

Example 1702 Assay for Determining MMP-8 Inhibition

The typical assay for MMP-8 activity is carried out in assay buffercomprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl₂ and 0.05%Brij-35. Different concentrations of tested compounds are prepared inassay buffer in 50 μL aliquots. 10 μL of a 50 nM stock solution ofactivated MMP-8 enzyme (Calbiochem, Cat. No. 444229) is added to thecompound solution. The mixture of enzyme and compound in assay buffer isthoroughly mixed and incubated for 10 min at 37° C. Upon the completionof incubation, the assay is started by addition of 40 μL of a 10 μMstock solution of OmniMMP fluorescent substrate (Biomol, Cat. No.P-126). The time-dependent increase in fluorescence is measured at the320 nm excitation and 390 nm emission by an automatic plate multireaderat 37° C. The IC₅₀ values are calculated from the initial reactionrates.

Example 1703 Assay for Determining MMP-12 Inhibition

The typical assay for MMP-12 activity is carried out in assay buffercomprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl₂ and 0.05%Brij-35. Different concentrations of tested compounds are prepared inassay buffer in 50 μL aliquots. 10 μL of a 50 nM stock solution of thecatalytic domain of MMP-12 enzyme (Biomol, Cat. No. SE-138) is added tothe compound solution. The mixture of enzyme and compound in assaybuffer is thoroughly mixed and incubated for 10 min at room temperature.Upon the completion of incubation, the assay is started by addition of40 μL of a 12.5 μM stock solution of OmniMMP fluorescent substrate(Biomol, Cat. No. P-126). The time-dependent increase in fluorescence ismeasured at the 320 nm excitation and 390 nm emission by automatic platemultireader at 37° C. The IC₅₀ values are calculated from the initialreaction rates.

Example 1704 Assay for Determining Aggrecanase-1 Inhibition

The typical assay for aggrecanase-1 activity is carried out in assaybuffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl₂ and0.05% Brij-35. Different concentrations of tested compounds are preparedin assay buffer in 50 μL aliquots. 10 μl of a 75 nM stock solution ofaggrecanase-1 (Invitek) is added to the compound solution. The mixtureof enzyme and compound in assay buffer is thoroughly mixed. The reactionis started by addition of 40 μL of a 250 nM stock solution ofaggrecan-IGD substrate (Invitek) and incubation at 37° C. for exact 15min. The reaction is stopped by addition of EDTA and the samples areanalysed by using aggrecanase ELISA (Invitek, InviLISA, Cat. No.30510111) according to the protocol of the supplier. Shortly: 100 μL ofeach proteolytic reaction are incubated in a pre-coated micro plate for90 min at room temperature. After 3 times washing, antibody-peroxidaseconjugate is added for 90 min at room temperature. After 5 timeswashing, the plate is incubated with TMB solution for 3 min at roomtemperature. The peroxidase reaction is stopped with sulfurous acid andthe absorbance is red at 450 nm. The IC₅₀ values are calculated from theabsorbance signal corresponding to residual aggrecanase activity.

Example 1705 Assay for Determining Inhibition of MMP-3 MediatedProteoglycan Degradation

The assay for MMP-3 activity is carried out in assay buffer comprised of50 mM MES, pH 6.0, 10 mM CaCl₂ and 0.05% Brij-35. Articular cartilage isisolated fresh from the first phalanges of adult cows and cut intopieces (˜3 mg). Bovine cartilage is incubated with 50 nM human MMP-3(Chemikon, cat. # 25020461) in presence or absence of inhibitor for 24 hat 37° C. Sulfated glycosaminoglycan (aggrecan) degradation products(sGAG) are detected in supernatant, using a modification of thecolorimetric DMMB (1,9-dimethylmethylene blue dye) assay (Billinghurstet al., 2000, Arthritis & Rheumatism, 43 (3), 664). 10 μL of the samplesor standard are added to 190 μL of the dye reagent in microtiter platewells, and the absorbance is measured at 525 nm immediately. All datapoints are performed in triplicates.

Example 1706 Assay for Determining Inhibition of MMP-3 MediatedPro-Collagenase 3 Activation

The assay for MMP-3 mediated activation of pro-collagenase 3(pro-MMP-13) is carried out in assay buffer comprised of 50 mM MES, pH6.0, 10 mM CaCl₂ and 0.05% Brij-35 (Nagase; J. Biol. Chem. 1994 Aug. 19;269(33):20952-7).

Different concentrations of tested compounds are prepared in assaybuffer in 5 μL aliquots. 10 μl of a 100 nM stock solution oftrypsin-activated (Knäuper V., et al., 1996 J. Biol. Chem. 2711544-1550) human pro-MMP-3 (Chemicon; CC 1035) is added to the compoundsolution. To this mixture, 35 μL of a 286 nM stock solution ofpro-collagenase 3 (Invitek; 30100803) is added to the mixture of enzymeand compound. The mixture is thoroughly mixed and incubated for 5 h at37° C. Upon the completion of incubation, 10 μL of the incubationmixture is added to 50 μL assay buffer comprised of 50 mM Tris, pH 7.5,150 mM NaCl, 5 mM CaCl₂ and 0.05% Brij-35 and the mixture is thoroughlymixed.

The assay to determine the MMP-13 activity is started by addition of 40μL of a 10 μM stock solution of MMP-13 fluorogenic substrate(Calbiochem, Cat. No. 444235) in assay buffer comprised of 50 mM Tris,pH 7.5, 150 mM NaCl, 5 mM CaCl₂ and 0.05% Brij-35 (Knäuper, V., et al.,1996. J. Biol. Chem. 271, 1544-1550). The time-dependent increase influorescence is measured at 320 nm excitation and 390 nm emission by anautomatic plate multireader at room temperature. The IC₅₀ values arecalculated from the initial reaction rates.

1. A compound having Formula (I):

wherein: R¹ is benzoxazinyl; wherein R¹ is optionally substituted one ormore times, or wherein R¹ is optionally substituted by one R¹⁶ group andoptionally substituted by one or more R⁹ groups; R² is selected fromhydrogen and alkyl, wherein alkyl is optionally substituted one or moretimes or R¹ and R² when taken together with the nitrogen to which theyare attached complete a 3- to 8-membered ring containing carbon atomsand optionally containing a heteroatom selected from O, S(O)_(x), orNR⁵⁰ and which is optionally substituted one or more times; R⁴ in eachoccurrence is independently selected from R¹⁰, hydrogen, alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, haloalkyl, CF₃,(C₀-C₆)-alkyl-COR¹⁰, (C₀-C₆)-alkyl-OR¹⁰, (C₀-C₆)-alkyl-NR¹⁰R¹¹,(C₀-C₆)-alkyl-NO₂, (C₀-C₆)-alkyl-CN, (C₀-C₆)-alkyl-S(O)_(y)OR¹⁰,(C₀-C₆)-alkyl-S(O)_(y)NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰CONR¹¹SO₂R³⁰,(C₀-C₆)-alkyl-S(O)_(x)R¹⁰, (C₀-C₆)-alkyl-OC(O)R¹⁰,(C₀-C₆)-alkyl-OC(O)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(═NR¹⁰)NR¹⁰R¹¹,(C₀-C₆)-alkyl-NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(O)OR¹⁰,(C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(O)NR¹⁰SO₂R¹¹,(C₀-C₆)-alkyl-C(O)—NR¹¹—CN, O—(C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹,S(O)_(x)—(C₀-C₆)-alkyl-C(O)OR¹⁰, S(O)_(x)—(C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹,(C₀-C₆)-alkyl-C(O)NR¹⁰—(C₀-C₆)-alkyl-NR¹⁰R¹¹,(C₀-C₆)-alkyl-NR¹⁰—C(O)R¹⁰, (C₀-C₆)-alkyl-NR¹⁰—C(O)OR¹⁰,(C₀-C₆)-alkyl-NR¹⁰—C(O)—NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰—S(O)_(y)NR¹⁰R¹¹,(C₀-C₆)-alkyl-NR¹⁰—S(O)_(y)R¹⁰, O—(C₀-C₆)-alkyl-aryl andO—(C₀-C₆)-alkyl-heteroaryl, wherein each R⁴ group is optionallysubstituted one or more times, or wherein each R⁴ group is optionallysubstituted by one or more R¹⁴ groups, or wherein optionally two R⁴groups, when taken together with the nitrogen or carbon to which theyare attached complete a 3- to 8-membered saturated ring or multicyclicring or unsaturated ring containing carbon atoms and optionallycontaining one or more heteroatom independently selected from O,S(O)_(x), N, or NR⁵⁰ and which is optionally substituted one or moretimes, or optionally two R⁴ groups taken together at one saturatedcarbon atom form ═O, ═S, ═NR¹⁰ or ═NOR¹⁰; R⁵ is independently selectedfrom hydrogen, alkyl, C(O)NR¹⁰R¹¹, aryl, arylalkyl, SO₂NR¹⁰R¹¹ andC(O)OR¹⁰ wherein alkyl, aryl and arylalkyl are optionally substitutedone or more times; R⁸ is independently selected from hydrogen, alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, R¹⁰ and NR¹⁰R¹¹ whereinalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionallysubstituted one or more times; R⁹ in each occurrence is independentlyselected from R¹⁰, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, halo, CHF₂, CF₃, OR¹⁰, SR¹⁰, COOR¹⁰, CH(CH₃)CO₂H,(C₀-C₆)-alkyl-COR¹⁰, (C₀-C₆)-alkyl-OR¹⁰, (C₀-C₆)-alkyl-NR¹⁰R¹¹,(C₀-C₆)-alkyl-NO₂, (C₀-C₆)-alkyl-CN, (C₀-C₆)-alkyl-S(O)_(y)R¹⁰,(C₀-C₆)-alkyl-P(O)₂OH, (C₀-C₆)-alkyl-S(O)_(y)NR¹⁰R¹¹,(C₀-C₆)-alkyl-NR¹⁰CONR¹¹SO₂R³⁰, (C₀-C₆)-alkyl-S(O)_(x)R¹⁰,(C₀-C₆)-alkyl-OC(O)R¹⁰, (C₀-C₆)-alkyl-OC(O)NR¹⁰R¹¹,(C₀-C₆)-alkyl-C(═NR¹⁰)NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰C(═NR¹¹)NR¹⁰R¹¹,(C₀-C₆)-alkyl-NR¹⁰C(═N—CN)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(═N—CN)NR¹⁰R¹¹,(C₀-C₆)-alkyl-NR¹⁰C(═N—NO₂)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(═N—NO₂)NR¹⁰R¹¹,(C₀-C₆)-alkyl-C(O)OR¹⁰, (C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹,(C₀-C₆)-alkyl-C(O)NR¹⁰SO₂R¹¹, C(O)NR¹⁰—(C₀-C₆)-alkyl-heteroaryl,C(O)NR¹⁰—(C₀-C₆)-alkyl-aryl, S(O)₂NR¹⁰—(C₀-C₆)-alkyl-aryl,S(O)₂NR¹⁰—(C₀-C₆)-alkyl-heteroaryl, S(O)₂NR¹⁰-alkyl,S(O)₂—(C₀-C₆)-alkyl-aryl, S(O)₂—(C₀-C₆)-alkyl-heteroaryl,(C₀-C₆)-alkyl-C(O)—NR¹¹—CN, O—(C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹,S(O)_(x)—(C₀-C₆)-alkyl-C(O)OR¹⁰, S(O)_(x)—(C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹,(C₀-C₆)-alkyl-C(O)NR¹⁰—(C₀-C₆)-alkyl-NR¹⁰R¹¹,(C₀-C₆)-alkyl-NR¹⁰—C(O)R¹⁰, (C₀-C₆)-alkyl-NR¹⁰—C(O)OR¹⁰,(C₀-C₆)-alkyl-NR¹⁰—C(O)—NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰—S(O)_(y)NR¹⁰R¹¹,(C₀-C₆)-alkyl-NR¹⁰—S(O)_(y)R¹¹, O—(C₀-C₆)-alkyl-aryl andO—(C₀-C₆)-alkyl-heteroaryl, wherein each R⁹ group is optionallysubstituted, or wherein each R⁹ group is optionally substituted by oneor more R¹⁴ groups; R¹⁰ and R¹¹ in each occurrence are independentlyselected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl,spiroheteroalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl andaminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl,heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, heterocycloalkyl,fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted oneor more times, or R¹⁰ and R¹¹ when taken together with the nitrogen towhich they are attached complete a 3- to 8-membered ring containingcarbon atoms and optionally containing a heteroatom selected from O,S(O)_(x), or NR⁵⁰ and which is optionally substituted one or more times;R¹⁴ is independently selected from hydrogen, alkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, heterocyclylalkyl and halo, whereinalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocyclylalkylare optionally substituted one or more times. R¹⁶ is selected fromcycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl,spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl,heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl,heterocycloalkyl fused heteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl,spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl,cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkylfused heteroarylalkyl, heterocycloalkyl fused heteroarylalkyl, (i) and(ii):

wherein cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl,spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl,heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl,heterocycloalkyl fused heteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl,spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl,cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkylfused heteroarylalkyl, and heterocycloalkyl fused heteroarylalkyl areoptionally substituted one or more times; R³⁰ is selected from alkyl and(C₀-C₆)-alkyl-aryl, wherein alkyl and aryl are optionally substituted;R⁵⁰ in each occurrence is independently selected from hydrogen, alkyl,aryl, heteroaryl, C(O)R⁸⁰, C(O)NR⁸⁰R⁸¹, SO₂R⁸⁰ and SO₂NR⁸⁰R⁸¹, whereinalkyl, aryl, and heteroaryl are optionally substituted one or moretimes; R⁸⁰ and R⁸¹ in each occurrence are independently selected fromhydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl,heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl and aminoalkyl are optionally substituted, or R⁸⁰ andR⁸¹ when taken together with the nitrogen to which they are attachedcomplete a 3- to 8-membered ring containing carbon atoms and optionallya heteroatom selected from O, S(O)_(x), —NH, and —N(alkyl) and which isoptionally substituted one or more times; E is selected from a bond,CR¹⁰R¹¹, O, NR⁵, S, S═O, S(═O)₂, C(═O), N(R¹⁰)(C═O), (C═O)N(R¹⁰),N(R¹⁰)S(═O)₂, S(═O)₂N(R¹⁰), C═N—OR¹¹, —C(R¹⁰R¹¹)C(R¹⁰R¹¹)—, —CH₂—W¹— and

L_(a) is independently selected from CR⁹ and N; L_(b) is independentlyselected from C and N with the proviso, that both L_(b) are not N, andthat the bond between L_(b) and L_(b) is optionally a double bond onlyif both L_(b) are C; Q is a 4- to 8-membered ring selected fromcycloalkyl, heterocycloalkyl or a 5- or 6-membered ring selected fromaryl and heteroaryl, wherein Q is optionally substituted one or moretimes, or wherein Q is optionally substituted one or more times with R⁴;U is selected from C(R⁵R¹⁰), NR⁵, O, S, S═O and S(═O)₂; W¹ is selectedfrom O, NR⁵, S, S═O, S(═O)₂, N(R¹⁰)(C═O), N(R¹⁰)S(═O)₂ and S(═O)₂N(R¹⁰);X is selected from a bond and (CR¹⁰R¹¹)_(w)E(CR¹⁰R¹¹)_(w); X¹ isindependently selected from O, S, NR¹⁰, N—CN, NCOR¹⁰, N—NO₂, orN—SO₂R¹⁰; g and h are independently selected from 0-2; w is selectedfrom 0-4; x is selected from 0 to 2; y is selected from 1 and 2; thedotted line optionally represents a double bond; and N-oxides,pharmaceutically acceptable salts, formulations, tautomers, racemicmixtures and stereoisomers thereof.
 2. A compound according to claim 1,having the structure:


3. A compound according to claim 1, selected from:


4. A compound according to claim 3, selected from:


5. A compound according to claim 1, wherein R¹ is selected from:

any of which are substituted by one or two substituents independentlyselected from C₁₋₂alkyl, C₁₋₂haloalkyl, halo, CN, OMe, OCF₃, or OCHF₂.6. A compound according to claim 1, wherein R¹ is selected from:


7. A compound according to claim 1, wherein R¹ is selected from:


8. A compound according to claim 1, wherein R¹ is:


9. A compound according to claim 1, selected from:

wherein R¹ is:


10. A compound according to claim 1, having the structure:

and N-oxides, pharmaceutically acceptable salts, formulations,tautomers, racemic mixtures and stereoisomers thereof.
 11. Apharmaceutical composition comprising an effective amount of thecompound selected from a compound according to claim
 1. 12. Apharmaceutical composition comprising: A) an effective amount of acompound according to claim 1; B) a pharmaceutically acceptable carrier;and C) a drug, agent or therapeutic selected from: (a) a diseasemodifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory drug;(c) a COX-2 selective inhibitor; (d) a COX-1 inhibitor; (e) animmunosuppressive; (f) a steroid; (g) a biological response modifier;and (h) a small molecule inhibitor of pro-inflammatory cytokineproduction.